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Qiu H, Li F, Prachyl H, Patino-Guerrero A, Rubart M, Zhu W. Insulin mitigates acute ischemia-induced atrial fibrillation and sinoatrial node dysfunction ex vivo. JCI Insight 2024; 10:e185961. [PMID: 39541171 PMCID: PMC11721304 DOI: 10.1172/jci.insight.185961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024] Open
Abstract
Acute atrial ischemia is a well-known cause of postoperative atrial fibrillation (POAF). However, mechanisms through which ischemia contributes to the development of POAF are not well understood. In this study, ex vivo Langendorff perfusion was used to induce acute ischemia/reperfusion in the heart to mimic POAF. Inducibility of atrial fibrillation (AF) was evaluated using programmed electrical stimulation and verified with open-atrium optical mapping. Compared with the control group without ischemia, 25 minutes of ischemia substantially increased the incidence of AF. The right atrium was more susceptible to AF than the left atrium. Administering insulin for 30 minutes before ischemia and during reperfusion with 25 minutes of ischemia greatly reduced the vulnerability to AF. However, insulin treatment during reperfusion only did not show substantial benefits against AF. Optical mapping studies showed that insulin mitigated ischemia-induced abnormal electrophysiology, including shortened action potential duration and effective refractory period, slowed conduction velocity, increased conduction heterogeneity, and altered calcium transients. In conclusion, insulin reduced the risk of acute ischemia/reperfusion-induced AF via improving the electrophysiology and calcium handling of atrial cardiomyocytes, which provides a potential therapy for POAF.
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Affiliation(s)
- Huiliang Qiu
- Departments of Cardiovascular Medicine and Physiology and Biomedical Engineering and Center for Regenerative Biotherapeutics, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Fan Li
- Departments of Cardiovascular Medicine and Physiology and Biomedical Engineering and Center for Regenerative Biotherapeutics, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Hannah Prachyl
- Departments of Cardiovascular Medicine and Physiology and Biomedical Engineering and Center for Regenerative Biotherapeutics, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Alejandra Patino-Guerrero
- Departments of Cardiovascular Medicine and Physiology and Biomedical Engineering and Center for Regenerative Biotherapeutics, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Michael Rubart
- Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Wuqiang Zhu
- Departments of Cardiovascular Medicine and Physiology and Biomedical Engineering and Center for Regenerative Biotherapeutics, Mayo Clinic Arizona, Scottsdale, Arizona, USA
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2
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Shaaban A, Scott SS, Greenlee AN, Binda N, Noor A, Webb A, Guo S, Purdy N, Pennza N, Habib A, Mohammad SJ, Smith SA. Atrial fibrillation in cancer, anticancer therapies, and underlying mechanisms. J Mol Cell Cardiol 2024; 194:118-132. [PMID: 38897563 PMCID: PMC11500699 DOI: 10.1016/j.yjmcc.2024.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 06/03/2024] [Accepted: 06/04/2024] [Indexed: 06/21/2024]
Abstract
Atrial fibrillation (AF) is a common arrhythmic complication in cancer patients and can be exacerbated by traditional cytotoxic and targeted anticancer therapies. Increased incidence of AF in cancer patients is independent of confounding factors, including preexisting myocardial arrhythmogenic substrates, type of cancer, or cancer stage. Mechanistically, AF is characterized by fast unsynchronized atrial contractions with rapid ventricular response, which impairs ventricular filling and results in various symptoms such as fatigue, chest pain, and shortness of breath. Due to increased blood stasis, a consequence of both cancer and AF, concern for stroke increases in this patient population. To compound matters, cardiotoxic anticancer therapies themselves promote AF; thereby exacerbating AF morbidity and mortality in cancer patients. In this review, we examine the relationship between AF, cancer, and cardiotoxic anticancer therapies with a focus on the shared molecular and electrophysiological mechanisms linking these disease processes. We also explore the potential role of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in the management of anticancer-therapy-induced AF.
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Affiliation(s)
- Adnan Shaaban
- The Ohio State University College of Medicine, Department of Internal Medicine, Columbus, OH 43210, USA
| | - Shane S Scott
- Medical Scientist Training Program, Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA; Bob and Corrinne Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Ashley N Greenlee
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA; Bob and Corrinne Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Nkongho Binda
- The Ohio State University College of Medicine, Department of Internal Medicine, Columbus, OH 43210, USA
| | - Ali Noor
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Averie Webb
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Shuliang Guo
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA; Bob and Corrinne Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Najhee Purdy
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA; Bob and Corrinne Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Nicholas Pennza
- Ohio University Heritage College of Osteopathic Medicine, Athens, OH 45701, USA
| | - Alma Habib
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA
| | - Somayya J Mohammad
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA; Bob and Corrinne Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Sakima A Smith
- The Ohio State University College of Medicine, Department of Internal Medicine, Columbus, OH 43210, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA; Bob and Corrinne Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
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Lee TI, Trang NN, Lee TW, Higa S, Kao YH, Chen YC, Chen YJ. Ketogenic Diet Regulates Cardiac Remodeling and Calcium Homeostasis in Diabetic Rat Cardiomyopathy. Int J Mol Sci 2023; 24:16142. [PMID: 38003332 PMCID: PMC10671812 DOI: 10.3390/ijms242216142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 11/02/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
A ketogenic diet (KD) might alleviate patients with diabetic cardiomyopathy. However, the underlying mechanism remains unclear. Myocardial function and arrhythmogenesis are closely linked to calcium (Ca2+) homeostasis. We investigated the effects of a KD on Ca2+ homeostasis and electrophysiology in diabetic cardiomyopathy. Male Wistar rats were created to have diabetes mellitus (DM) using streptozotocin (65 mg/kg, intraperitoneally), and subsequently treated for 6 weeks with either a normal diet (ND) or a KD. Our electrophysiological and Western blot analyses assessed myocardial Ca2+ homeostasis in ventricular preparations in vivo. Unlike those on the KD, DM rats treated with an ND exhibited a prolonged QTc interval and action potential duration. Compared to the control and DM rats on the KD, DM rats treated with an ND also showed lower intracellular Ca2+ transients, sarcoplasmic reticular Ca2+ content, sodium (Na+)-Ca2+ exchanger currents (reverse mode), L-type Ca2+ contents, sarcoplasmic reticulum ATPase contents, Cav1.2 contents. Furthermore, these rats exhibited elevated ratios of phosphorylated to total proteins across multiple Ca2+ handling proteins, including ryanodine receptor 2 (RyR2) at serine 2808, phospholamban (PLB)-Ser16, and calmodulin-dependent protein kinase II (CaMKII). Additionally, DM rats treated with an ND demonstrated a higher frequency and incidence of Ca2+ leak, cytosolic reactive oxygen species, Na+/hydrogen-exchanger currents, and late Na+ currents than the control and DM rats on the KD. KD treatment may attenuate the effects of DM-dysregulated Na+ and Ca2+ homeostasis, contributing to its cardioprotection in DM.
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Affiliation(s)
- Ting-I Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (T.-I.L.); (T.-W.L.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
| | | | - Ting-Wei Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (T.-I.L.); (T.-W.L.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
| | - Satoshi Higa
- Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Makiminato Urasoe City, Okinawa 901-2131, Japan;
| | - Yu-Hsun Kao
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
| | - Yao-Chang Chen
- Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan
| | - Yi-Jen Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
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Ghafary I, Kim CK, Roth E, Lu M, Taub EM, Lee S, Cohen I, Lu Z. The association of QTc prolongation with cardiovascular events in cancer patients taking tyrosine kinase inhibitors (TKIs). CARDIO-ONCOLOGY (LONDON, ENGLAND) 2023; 9:25. [PMID: 37208762 DOI: 10.1186/s40959-023-00178-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Accepted: 05/12/2023] [Indexed: 05/21/2023]
Abstract
OBJECTIVE To investigate the association between stages of QTc prolongation and the risk of cardiac events among patients on TKIs. METHODS This was a retrospective cohort study performed at an academic tertiary care center of cancer patients who were taking TKIs or not taking TKIs. Patients with two recorded ECGs between January 1, 2009, and December 31, 2019, were selected from an electronic database. The QTc duration > 450ms was determined as prolonged. The association between QTc prolongation progression and events of cardiovascular disease were compared. RESULTS This study included a total of 451 patients with 41.2% of patients taking TKIs. During a median follow up period of 3.1 years, 49.5% subjects developed CVD and 5.4% subjects suffered cardiac death in patient using TKIs (n = 186); the corresponding rates are 64.2% and 1.2% for patients not on TKIs (n = 265), respectively. Among patient on TKIs, 4.8% of subjects developed stroke, 20.4% of subjects suffered from heart failure (HF) and 24.2% of subjects had myocardial infarction (MI); corresponding incidence are 6.8%, 26.8% and 30.6% in non-TKIs. When patients were regrouped to TKIs versus non-TKIs with and without diabetes, there was no significant difference in the incidence of cardiac events among all groups. Adjusted Cox proportional hazards models were applied to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). There is a significant increased risk of HF events (HR, 95% CI: 2.12, 1.36-3.32) and MI events (HR, 95% CI: 1.78, 1.16-2.73) during the 1st visit. There are also trends for an increased incidence of cardiac adverse events associated with QTc prolongation among patient with QTc > 450ms, however the difference is not statistically significant. Increased cardiac adverse events in patients with QTc prolongation were reproduced during the 2nd visit and the incidence of heart failure was significantly associated with QTc prolongation(HR, 95% CI: 2.94, 1.73-5.0). CONCLUSION There is a significant increased QTc prolongation in patients taking TKIs. QTc prolongation caused by TKIs is associated with an increased risk of cardiac events.
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Affiliation(s)
- Ismail Ghafary
- Department of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Chang-Kyung Kim
- Department of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Eric Roth
- Department of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Michael Lu
- Department of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Erin M Taub
- Department of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Susan Lee
- Department of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Ira Cohen
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Zhongju Lu
- Department of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA.
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Emerging Therapy for Diabetic Cardiomyopathy: From Molecular Mechanism to Clinical Practice. Biomedicines 2023; 11:biomedicines11030662. [PMID: 36979641 PMCID: PMC10045486 DOI: 10.3390/biomedicines11030662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/08/2023] [Accepted: 02/11/2023] [Indexed: 02/24/2023] Open
Abstract
Diabetic cardiomyopathy is characterized by abnormal myocardial structure or performance in the absence of coronary artery disease or significant valvular heart disease in patients with diabetes mellitus. The spectrum of diabetic cardiomyopathy ranges from subtle myocardial changes to myocardial fibrosis and diastolic function and finally to symptomatic heart failure. Except for sodium–glucose transport protein 2 inhibitors and possibly bariatric and metabolic surgery, there is currently no specific treatment for this distinct disease entity in patients with diabetes. The molecular mechanism of diabetic cardiomyopathy includes impaired nutrient-sensing signaling, dysregulated autophagy, impaired mitochondrial energetics, altered fuel utilization, oxidative stress and lipid peroxidation, advanced glycation end-products, inflammation, impaired calcium homeostasis, abnormal endothelial function and nitric oxide production, aberrant epidermal growth factor receptor signaling, the activation of the renin–angiotensin–aldosterone system and sympathetic hyperactivity, and extracellular matrix accumulation and fibrosis. Here, we summarize several important emerging treatments for diabetic cardiomyopathy targeting specific molecular mechanisms, with evidence from preclinical studies and clinical trials.
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Gao J, Xue G, Zhan G, Wang X, Li J, Yang X, Xia Y. Benefits of SGLT2 inhibitors in arrhythmias. Front Cardiovasc Med 2022; 9:1011429. [PMID: 36337862 PMCID: PMC9631490 DOI: 10.3389/fcvm.2022.1011429] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 10/04/2022] [Indexed: 09/25/2023] Open
Abstract
Some studies have shown that sodium-glucose cotransporter (SGLT) 2 inhibitors can definitively attenuate the occurrence of cardiovascular diseases such as heart failure (HF), dilated cardiomyopathy (DCM), and myocardial infarction. With the development of research, SGLT2 inhibitors can also reduce the risk of arrhythmias. So in this review, how SGLT2 inhibitors play a role in reducing the risk of arrhythmia from the perspective of electrical remodeling and structural remodeling are explored and then the possible mechanisms are discussed. Specifically, we focus on the role of SGLT2 inhibitors in Na+ and Ca2 + homeostasis and the transients of Na+ and Ca2 +, which could affect electrical remodeling and then lead to arrythmia. We also discuss the protective role of SGLT2 inhibitors in structural remodeling from the perspective of fibrosis, inflammation, oxidative stress, and apoptosis. Ultimately, it is clear that SGLT2 inhibitors have significant benefits on cardiovascular diseases such as HF, myocardial hypertrophy and myocardial infarction. It can be expected that SGLT2 inhibitors can reduce the risk of arrhythmia.
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Affiliation(s)
| | | | | | | | | | | | - Yunlong Xia
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
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7
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Young WJ, Lahrouchi N, Isaacs A, Duong T, Foco L, Ahmed F, Brody JA, Salman R, Noordam R, Benjamins JW, Haessler J, Lyytikäinen LP, Repetto L, Concas MP, van den Berg ME, Weiss S, Baldassari AR, Bartz TM, Cook JP, Evans DS, Freudling R, Hines O, Isaksen JL, Lin H, Mei H, Moscati A, Müller-Nurasyid M, Nursyifa C, Qian Y, Richmond A, Roselli C, Ryan KA, Tarazona-Santos E, Thériault S, van Duijvenboden S, Warren HR, Yao J, Raza D, Aeschbacher S, Ahlberg G, Alonso A, Andreasen L, Bis JC, Boerwinkle E, Campbell A, Catamo E, Cocca M, Cutler MJ, Darbar D, De Grandi A, De Luca A, Ding J, Ellervik C, Ellinor PT, Felix SB, Froguel P, Fuchsberger C, Gögele M, Graff C, Graff M, Guo X, Hansen T, Heckbert SR, Huang PL, Huikuri HV, Hutri-Kähönen N, Ikram MA, Jackson RD, Junttila J, Kavousi M, Kors JA, Leal TP, Lemaitre RN, Lin HJ, Lind L, Linneberg A, Liu S, MacFarlane PW, Mangino M, Meitinger T, Mezzavilla M, Mishra PP, Mitchell RN, Mononen N, Montasser ME, Morrison AC, Nauck M, Nauffal V, Navarro P, Nikus K, Pare G, Patton KK, Pelliccione G, Pittman A, Porteous DJ, Pramstaller PP, Preuss MH, Raitakari OT, Reiner AP, Ribeiro ALP, et alYoung WJ, Lahrouchi N, Isaacs A, Duong T, Foco L, Ahmed F, Brody JA, Salman R, Noordam R, Benjamins JW, Haessler J, Lyytikäinen LP, Repetto L, Concas MP, van den Berg ME, Weiss S, Baldassari AR, Bartz TM, Cook JP, Evans DS, Freudling R, Hines O, Isaksen JL, Lin H, Mei H, Moscati A, Müller-Nurasyid M, Nursyifa C, Qian Y, Richmond A, Roselli C, Ryan KA, Tarazona-Santos E, Thériault S, van Duijvenboden S, Warren HR, Yao J, Raza D, Aeschbacher S, Ahlberg G, Alonso A, Andreasen L, Bis JC, Boerwinkle E, Campbell A, Catamo E, Cocca M, Cutler MJ, Darbar D, De Grandi A, De Luca A, Ding J, Ellervik C, Ellinor PT, Felix SB, Froguel P, Fuchsberger C, Gögele M, Graff C, Graff M, Guo X, Hansen T, Heckbert SR, Huang PL, Huikuri HV, Hutri-Kähönen N, Ikram MA, Jackson RD, Junttila J, Kavousi M, Kors JA, Leal TP, Lemaitre RN, Lin HJ, Lind L, Linneberg A, Liu S, MacFarlane PW, Mangino M, Meitinger T, Mezzavilla M, Mishra PP, Mitchell RN, Mononen N, Montasser ME, Morrison AC, Nauck M, Nauffal V, Navarro P, Nikus K, Pare G, Patton KK, Pelliccione G, Pittman A, Porteous DJ, Pramstaller PP, Preuss MH, Raitakari OT, Reiner AP, Ribeiro ALP, Rice KM, Risch L, Schlessinger D, Schotten U, Schurmann C, Shen X, Shoemaker MB, Sinagra G, Sinner MF, Soliman EZ, Stoll M, Strauch K, Tarasov K, Taylor KD, Tinker A, Trompet S, Uitterlinden A, Völker U, Völzke H, Waldenberger M, Weng LC, Whitsel EA, Wilson JG, Avery CL, Conen D, Correa A, Cucca F, Dörr M, Gharib SA, Girotto G, Grarup N, Hayward C, Jamshidi Y, Järvelin MR, Jukema JW, Kääb S, Kähönen M, Kanters JK, Kooperberg C, Lehtimäki T, Lima-Costa MF, Liu Y, Loos RJF, Lubitz SA, Mook-Kanamori DO, Morris AP, O'Connell JR, Olesen MS, Orini M, Padmanabhan S, Pattaro C, Peters A, Psaty BM, Rotter JI, Stricker B, van der Harst P, van Duijn CM, Verweij N, Wilson JF, Arking DE, Ramirez J, Lambiase PD, Sotoodehnia N, Mifsud B, Newton-Cheh C, Munroe PB. Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways. Nat Commun 2022; 13:5144. [PMID: 36050321 PMCID: PMC9436946 DOI: 10.1038/s41467-022-32821-z] [Show More Authors] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 08/17/2022] [Indexed: 11/10/2022] Open
Abstract
The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
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Affiliation(s)
- William J Young
- William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London, UK
- Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS trust, London, UK
| | - Najim Lahrouchi
- Amsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Cardiovascular Research Center, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Aaron Isaacs
- Deptartment of Physiology, Cardiovascular Research Institute Maastricht CARIM, Maastricht University, Maastricht, The Netherlands
- Maastricht Center for Systems Biology MaCSBio, Maastricht University, Maastricht, The Netherlands
| | - ThuyVy Duong
- McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Luisa Foco
- Eurac Research, Institute for Biomedicine affiliated with the University of Lübeck, Bolzano, Italy
| | - Farah Ahmed
- William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London, UK
| | - Jennifer A Brody
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Reem Salman
- William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London, UK
| | - Raymond Noordam
- Department of Internal Medicine, section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
| | - Jan-Walter Benjamins
- University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands
| | - Jeffrey Haessler
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Leo-Pekka Lyytikäinen
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
- Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Linda Repetto
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland
| | - Maria Pina Concas
- Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy
| | - Marten E van den Berg
- Department of Epidemiology, Erasmus MC - University Medical Center, Rotterdam, The Netherlands
| | - Stefan Weiss
- DZHK German Centre for Cardiovascular Research; partner site Greifswald, Greifswald, Germany
- Interfaculty Institute for Genetics and Functional Genomics; Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Antoine R Baldassari
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, USA
| | - Traci M Bartz
- Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, Seattle, WA, USA
| | - James P Cook
- Department of Health Data Science, University of Liverpool, Liverpool, UK
| | - Daniel S Evans
- California Pacific Medical Center, Research Institute, San Francisco, CA, USA
| | - Rebecca Freudling
- Department of Cardiology, University Hospital, LMU Munich, Munich, Germany
- Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Oliver Hines
- Genetics Research Centre, St George's University of London, London, UK
- Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK
| | - Jonas L Isaksen
- Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Honghuang Lin
- National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA
- Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Hao Mei
- Department of Data Science, University of Mississippi Medical Center, Jackson, USA
| | - Arden Moscati
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Martina Müller-Nurasyid
- Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
- IBE, Faculty of Medicine, LMU Munich, Munich, Germany
- Institute of Medical Biostatistics, Epidemiology and Informatics IMBEI, University Medical Center, Johannes Gutenberg University, Mainz, Germany
| | - Casia Nursyifa
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Yong Qian
- Translational Gerontology Branch, National Institute on Aging, National Institute of Health, Baltimore, US
| | - Anne Richmond
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - Carolina Roselli
- University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands
- Cardiovascular Disease Initiative, Broad Institute, Cambridge, MA, USA
| | - Kathleen A Ryan
- Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA
- Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Eduardo Tarazona-Santos
- Department of Genetics, Ecology and Evolution, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte/Minas Gerais, Brazil
| | - Sébastien Thériault
- Population Health Research Institute, McMaster University, Hamilton, Canada
- Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Quebec, Canada
| | - Stefan van Duijvenboden
- William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London, UK
- Institute of Cardiovascular Sciences, University of College London, London, UK
| | - Helen R Warren
- William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London, UK
- NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Jie Yao
- Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Dania Raza
- William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London, UK
- Brighton and Sussex Medical School, Brighton, UK
| | - Stefanie Aeschbacher
- Cardiovascular Research Institute Basel, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Gustav Ahlberg
- Laboratory for Molecular Cardiology, The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Alvaro Alonso
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Laura Andreasen
- Laboratory for Molecular Cardiology, The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Joshua C Bis
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Eric Boerwinkle
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
| | - Archie Campbell
- Usher Institute, University of Edinburgh, Nine, Edinburgh Bioquarter, 9 Little France Road, Edinburgh, UK
- Health Data Research UK, University of Edinburgh, Nine, Edinburgh Bioquarter, 9 Little France Road, Edinburgh, UK
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - Eulalia Catamo
- Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy
| | - Massimiliano Cocca
- Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy
| | - Michael J Cutler
- Intermountain Heart Institute, Intermountain Medical Center, Murray, UT, USA
| | - Dawood Darbar
- Department of Medicine, University of Illinois at Chicago, Chicago, USA
| | - Alessandro De Grandi
- Eurac Research, Institute for Biomedicine affiliated with the University of Lübeck, Bolzano, Italy
| | - Antonio De Luca
- Cardiothoracovascular Department, ASUGI, University of Trieste, Trieste, Italy
| | - Jun Ding
- Translational Gerontology Branch, National Institute on Aging, National Institute of Health, Baltimore, US
| | - Christina Ellervik
- Department of Data and Data Support, Region Zealand, 4180, Sorø, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark
- Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Patrick T Ellinor
- Cardiovascular Disease Initiative, Broad Institute, Cambridge, MA, USA
- Demoulas Center for Cardiac Arrhythmias and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
| | - Stephan B Felix
- DZHK German Centre for Cardiovascular Research; partner site Greifswald, Greifswald, Germany
- Department of Internal Medicine B - Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine; University Medicine Greifswald, Greifswald, Germany
| | - Philippe Froguel
- Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
- University of Lille Nord de France, Lille, France
- CNRS UMR8199, Institut Pasteur de Lille, Lille, France
| | - Christian Fuchsberger
- Eurac Research, Institute for Biomedicine affiliated with the University of Lübeck, Bolzano, Italy
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, USA
- Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, USA
| | - Martin Gögele
- Eurac Research, Institute for Biomedicine affiliated with the University of Lübeck, Bolzano, Italy
| | - Claus Graff
- Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Mariaelisa Graff
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Xiuqing Guo
- Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
- Department of Pediatrics/Harbor-UCLA Medical Center, Torrance, CA, USA
- Department of Pediatrics/David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Susan R Heckbert
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
- Department of Epidemiology/University of Washington, Seattle, WA, USA
| | - Paul L Huang
- Cardiology Division and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Heikki V Huikuri
- Research Unit of Internal Medicine, Medical Research Center Oulu, University of Oulu and University Hospital of Oulu, Oulu, Finland
| | - Nina Hutri-Kähönen
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
- Department of Pediatrics, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Tampere Centre for Skills Training and Simulation, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - M Arfan Ikram
- Department of Epidemiology, Erasmus MC - University Medical Center, Rotterdam, The Netherlands
| | - Rebecca D Jackson
- Center for Clinical and Translational Science, Ohio State Medical Center, Columbus, OH, USA
| | - Juhani Junttila
- Research Unit of Internal Medicine, Medical Research Center Oulu, University of Oulu and University Hospital of Oulu, Oulu, Finland
| | - Maryam Kavousi
- Department of Epidemiology, Erasmus MC - University Medical Center, Rotterdam, The Netherlands
| | - Jan A Kors
- Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, NL, The Netherlands
| | - Thiago P Leal
- Department of Genetics, Ecology and Evolution, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte/Minas Gerais, Brazil
- Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Rozenn N Lemaitre
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Henry J Lin
- Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
- Department of Pediatrics/Harbor-UCLA Medical Center, Torrance, CA, USA
- Department of Pediatrics/David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Lars Lind
- Deptartment of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Allan Linneberg
- Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Simin Liu
- Center for Global Cardiometabolic Health, Departments of Epidemiology, Medicine and Surgery, Brown University, Providence, USA
| | - Peter W MacFarlane
- Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Massimo Mangino
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
- NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, UK
| | - Thomas Meitinger
- Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
- Institute of Human Genetics, Technical University of Munich, Munich, Germany
- DZHK (German Centre for Cardiovascular Research, partner site: Munich Heart Alliance, Munich, Germany
| | - Massimo Mezzavilla
- Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy
| | - Pashupati P Mishra
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
- Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Rebecca N Mitchell
- McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nina Mononen
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
- Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - May E Montasser
- Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA
- Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Alanna C Morrison
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Matthias Nauck
- DZHK German Centre for Cardiovascular Research; partner site Greifswald, Greifswald, Germany
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Victor Nauffal
- Cardiovascular Disease Initiative, Broad Institute, Cambridge, MA, USA
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Pau Navarro
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland
| | - Kjell Nikus
- Department of Cardiology, Heart Center, Tampere University Hospital, Tampere, Finland
- Department of Cardiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Guillaume Pare
- Population Health Research Institute, McMaster University, Hamilton, Canada
| | - Kristen K Patton
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Giulia Pelliccione
- Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy
| | - Alan Pittman
- Genetics Research Centre, St George's University of London, London, UK
| | - David J Porteous
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
| | - Peter P Pramstaller
- Eurac Research, Institute for Biomedicine affiliated with the University of Lübeck, Bolzano, Italy
- Department of Neurology, University of Lübeck, Lübeck, Germany
| | - Michael H Preuss
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Olli T Raitakari
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
- Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
- Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
| | - Alexander P Reiner
- Department of Epidemiology/University of Washington, Seattle, WA, USA
- Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA
| | - Antonio Luiz P Ribeiro
- Department of Internal Medicine, Faculdade de Medicina, Universidade Federal de Minas Gerais, Brazil, Belo Horizonte, Minas Gerais, Brazil
- Cardiology Service and Telehealth Center, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, Belo Horizonte, Minas Gerais, Brazil
| | - Kenneth M Rice
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Lorenz Risch
- Labormedizinisches zentrum Dr. Risch, Vaduz, Liechtenstein
- Faculty of Medical Sciences, Private University in the Principality of Liechtenstein, Triesen, Liechtenstein
- Center of Laboratory Medicine, University Institute of Clinical Chemistry, University of Bern, Inselspital, Bern, Switzerland
| | - David Schlessinger
- Laboratory of Genetics and Genomics, National Institute on Aging, National Institute of Health, Baltimore, US
| | - Ulrich Schotten
- Deptartment of Physiology, Cardiovascular Research Institute Maastricht CARIM, Maastricht University, Maastricht, The Netherlands
| | - Claudia Schurmann
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Digital Health Center, Hasso Plattner Institute, University of Potsdam, Potsdam, Germany
- Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Xia Shen
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Greater Bay Area Institute of Precision Medicine Guangzhou, Fudan University, Nansha District, Guangzhou, China
| | - M Benjamin Shoemaker
- Department of Medicine, Division of Cardiovascular Medicine, Arrhythmia Section, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Gianfranco Sinagra
- Cardiothoracovascular Department, ASUGI, University of Trieste, Trieste, Italy
| | - Moritz F Sinner
- Department of Cardiology, University Hospital, LMU Munich, Munich, Germany
- DZHK (German Centre for Cardiovascular Research, partner site: Munich Heart Alliance, Munich, Germany
| | - Elsayed Z Soliman
- Epidemiological Cardiology Research Center EPICARE, Wake Forest School of Medicine, Winston Salem, USA
| | - Monika Stoll
- Maastricht Center for Systems Biology MaCSBio, Maastricht University, Maastricht, The Netherlands
- Dept. of Biochemistry, Cardiovascular Research Institute Maastricht CARIM, Maastricht University, Maastricht, NL, The Netherlands
- Institute of Human Genetics, Genetic Epidemiology, University of Muenster, Muenster, Germany
| | - Konstantin Strauch
- Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
- IBE, Faculty of Medicine, LMU Munich, Munich, Germany
- Institute of Medical Biostatistics, Epidemiology and Informatics IMBEI, University Medical Center, Johannes Gutenberg University, Mainz, Germany
| | - Kirill Tarasov
- Laboratory of Cardiovascular Sciences, National Institute on Aging, National Institute of Health, Baltimore, US
| | - Kent D Taylor
- Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
- Department of Pediatrics/Harbor-UCLA Medical Center, Torrance, CA, USA
- Department of Pediatrics/David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Andrew Tinker
- William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London, UK
- NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Stella Trompet
- Department of Internal Medicine, section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
- Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Uwe Völker
- DZHK German Centre for Cardiovascular Research; partner site Greifswald, Greifswald, Germany
- Interfaculty Institute for Genetics and Functional Genomics; Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Henry Völzke
- DZHK German Centre for Cardiovascular Research; partner site Greifswald, Greifswald, Germany
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Melanie Waldenberger
- DZHK (German Centre for Cardiovascular Research, partner site: Munich Heart Alliance, Munich, Germany
- Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Lu-Chen Weng
- Cardiovascular Disease Initiative, Broad Institute, Cambridge, MA, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
| | - Eric A Whitsel
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, USA
- Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA
| | - James G Wilson
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA
- Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, USA
| | - Christy L Avery
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, USA
| | - David Conen
- Population Health Research Institute, McMaster University, Hamilton, Canada
| | - Adolfo Correa
- Departments of Medicine, Pediatrics and Population Health Science, University of Mississippi Medical Center, Jackson, USA
| | - Francesco Cucca
- Institute of Genetic and Biomedical Rsearch, Italian National Research Council, Monserrato, Italy
| | - Marcus Dörr
- DZHK German Centre for Cardiovascular Research; partner site Greifswald, Greifswald, Germany
- Department of Internal Medicine B - Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine; University Medicine Greifswald, Greifswald, Germany
| | - Sina A Gharib
- Center for Lung Biology, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA, USA
| | - Giorgia Girotto
- Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy
- Department of Medical Sciences, University of Trieste, Trieste, Italy
| | - Niels Grarup
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Caroline Hayward
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - Yalda Jamshidi
- Genetics Research Centre, St George's University of London, London, UK
| | - Marjo-Riitta Järvelin
- Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
- Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland
- Department of Epidemiology and Biostatistics, MRC PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
- Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK
| | - J Wouter Jukema
- Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
- Netherlands Heart Institute, Utrecht, The Netherlands
| | - Stefan Kääb
- Department of Cardiology, University Hospital, LMU Munich, Munich, Germany
- DZHK (German Centre for Cardiovascular Research, partner site: Munich Heart Alliance, Munich, Germany
| | - Mika Kähönen
- Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland
- Department of Clinical Physiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Jørgen K Kanters
- Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Charles Kooperberg
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
- Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | | | - Yongmei Liu
- Department of Medicine, Duke University, Durham, NC, USA
| | - Ruth J F Loos
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Steven A Lubitz
- Cardiovascular Disease Initiative, Broad Institute, Cambridge, MA, USA
- Demoulas Center for Cardiac Arrhythmias and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
| | - Dennis O Mook-Kanamori
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands
| | - Andrew P Morris
- Department of Health Data Science, University of Liverpool, Liverpool, UK
- Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Jeffrey R O'Connell
- Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA
- Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | | | - Michele Orini
- Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS trust, London, UK
- Institute of Cardiovascular Sciences, University of College London, London, UK
| | - Sandosh Padmanabhan
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Cristian Pattaro
- Eurac Research, Institute for Biomedicine affiliated with the University of Lübeck, Bolzano, Italy
| | - Annette Peters
- Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
- DZHK (German Centre for Cardiovascular Research, partner site: Munich Heart Alliance, Munich, Germany
| | - Bruce M Psaty
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
- Department of Epidemiology/University of Washington, Seattle, WA, USA
- Health Systems and Population Health, University of Washington, Seattle, WA, USA
| | - Jerome I Rotter
- Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
- Department of Pediatrics/Harbor-UCLA Medical Center, Torrance, CA, USA
- Departments of Pediatrics and Human Genetics/David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Bruno Stricker
- Department of Epidemiology, Erasmus MC - University Medical Center, Rotterdam, The Netherlands
| | - Pim van der Harst
- University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands
- Department of Cardiology, Heart and Lung Division, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Cornelia M van Duijn
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Niek Verweij
- University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands
| | - James F Wilson
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland
| | - Dan E Arking
- McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Julia Ramirez
- William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London, UK
- Institute of Cardiovascular Sciences, University of College London, London, UK
| | - Pier D Lambiase
- Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS trust, London, UK
- Institute of Cardiovascular Sciences, University of College London, London, UK
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Borbala Mifsud
- William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London, UK
- Genomics and Translational Biomedicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Christopher Newton-Cheh
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
- Cardiovascular Research Center, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
| | - Patricia B Munroe
- William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London, UK.
- NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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Jaquenod De Giusti C, Palomeque J, Mattiazzi A. Ca 2+ mishandling and mitochondrial dysfunction: a converging road to prediabetic and diabetic cardiomyopathy. Pflugers Arch 2022; 474:33-61. [PMID: 34978597 PMCID: PMC8721633 DOI: 10.1007/s00424-021-02650-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 11/17/2021] [Accepted: 12/03/2021] [Indexed: 12/16/2022]
Abstract
Diabetic cardiomyopathy is defined as the myocardial dysfunction that suffers patients with diabetes mellitus (DM) in the absence of hypertension and structural heart diseases such as valvular or coronary artery dysfunctions. Since the impact of DM on cardiac function is rather silent and slow, early stages of diabetic cardiomyopathy, known as prediabetes, are poorly recognized, and, on many occasions, cardiac illness is diagnosed only after a severe degree of dysfunction was reached. Therefore, exploration and recognition of the initial pathophysiological mechanisms that lead to cardiac dysfunction in diabetic cardiomyopathy are of vital importance for an on-time diagnosis and treatment of the malady. Among the complex and intricate mechanisms involved in diabetic cardiomyopathy, Ca2+ mishandling and mitochondrial dysfunction have been described as pivotal early processes. In the present review, we will focus on these two processes and the molecular pathway that relates these two alterations to the earlier stages and the development of diabetic cardiomyopathy.
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Affiliation(s)
- Carolina Jaquenod De Giusti
- Centro de Investigaciones Cardiovasculares, CCT-La Plata-CONICET, Facultad de Cs. Médicas, UNLP, La Plata, Argentina
| | - Julieta Palomeque
- Centro de Investigaciones Cardiovasculares, CCT-La Plata-CONICET, Facultad de Cs. Médicas, UNLP, La Plata, Argentina
| | - Alicia Mattiazzi
- Centro de Investigaciones Cardiovasculares, CCT-La Plata-CONICET, Facultad de Cs. Médicas, UNLP, La Plata, Argentina.
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9
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Lu Z, Luu Y, Ip J, Husain I, Lu M, Kim CK, Yang P, Chu D, Lin R, Cohen I, Kaell A. The Risk of QTc Prolongation in Non-Diabetic and Diabetic Patients Taking Tyrosine Kinase Inhibitors (TKIs)- A Patient Safety Project at a Private Oncology Practice. J Community Hosp Intern Med Perspect 2021; 11:799-807. [PMID: 34804394 PMCID: PMC8604509 DOI: 10.1080/20009666.2021.1978652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Objective: To assess the prevalence of QTc prolongation in both non-diabetic and diabetic patients on TKIs. Some TKIs have been reported to cause QTc prolongation, which is prevalent in diabetes. However, there is no Risk Evaluation and Mitigation Strategy using series ECG to monitor those patients. Methods:
Patients taking TKIs, with two ECGs recorded between 1 January 2010 and 31 December 2017 were selected from the electronic database. The QTc duration >450 ms was determined as prolonged. Percentage of QTc prolongation on participants were compared using Chi-Square test. Results:
This study included 313 patients (age 66.1 ± 0.8 years and 57.5% are female) taking TKIs. In non-Diabetic patients, the prevalence of QTc prolongation is 19.1% (n = 253) before and 34.8% (n = 253) after treatment with TKIs (p < 0.001), respectively. In diabetic patients, the prevalence of QTc prolongation is 21.7% (n = 60) before and 40% (n = 60) after treatment with TKIs (p = 0.03), respectively. In addition, we examined the effect of modifying risk factors for cardiovascular disease (CVD) on the prevalence of QTc prolongation caused by TKIs. In non-diabetic patients, the prevalence of QTc prolongation is 33.3% (n = 57) before and 34.2% (n = 196) after risk factors modification (p = 0.91), respectively. In diabetic patients, the prevalence of QTc prolongation is 50% (n = 24) before and 33.3% (n = 36) after risk factors modification (p = 0.20), respectively. Conclusion:
Use of TKIs is associated with a significantly increased risk of QTc prolongation for patients, particularly when patients are diabetic. Modification of risk factors for CVD does not significantly affect the prevalence of QTc prolongation caused by TKIs.
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Affiliation(s)
- Zhongju Lu
- Department of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Ying Luu
- Department of Internal Medicine, John T. Mather Memorial Hospital, Port Jefferson, NY, USA
| | - Jack Ip
- Department of Internal Medicine, John T. Mather Memorial Hospital, Port Jefferson, NY, USA
| | - Imran Husain
- Department of Internal Medicine, John T. Mather Memorial Hospital, Port Jefferson, NY, USA
| | - Michael Lu
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USA
| | - Chang-Kyung Kim
- Department of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Peng Yang
- Department of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - David Chu
- New York Cancer & Blood Specialists, East Setauket, NY, USA
| | - Richard Lin
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USA
| | - Ira Cohen
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USA
| | - Alan Kaell
- Department of Internal Medicine, John T. Mather Memorial Hospital, Port Jefferson, NY, USA
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10
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El Hayek MS, Ernande L, Benitah JP, Gomez AM, Pereira L. The role of hyperglycaemia in the development of diabetic cardiomyopathy. Arch Cardiovasc Dis 2021; 114:748-760. [PMID: 34627704 DOI: 10.1016/j.acvd.2021.08.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 08/02/2021] [Accepted: 08/04/2021] [Indexed: 01/08/2023]
Abstract
Diabetes mellitus is a metabolic disorder with a chronic hyperglycaemic state. Cardiovascular diseases are the primary cause of mortality in patients with diabetes. Increasing evidence supports the existence of diabetic cardiomyopathy, a cardiac dysfunction with impaired cardiac contraction and relaxation, independent of coronary and/or valvular complications. Diabetic cardiomyopathy can lead to heart failure. Several preclinical and clinical studies have aimed to decipher the underlying mechanisms of diabetic cardiomyopathy. Among all the co-factors, hyperglycaemia seems to play an important role in this pathology. Hyperglycaemia has been shown to alter cardiac metabolism and function through several deleterious mechanisms, such as oxidative stress, inflammation, accumulation of advanced glycated end-products and upregulation of the hexosamine biosynthesis pathway. These mechanisms are responsible for the activation of hypertrophic pathways, epigenetic modifications, mitochondrial dysfunction, cell apoptosis, fibrosis and calcium mishandling, leading to cardiac stiffness, as well as contractile and relaxation dysfunction. This review aims to describe the hyperglycaemic-induced alterations that participate in diabetic cardiomyopathy, and their correlation with the severity of the disease and patient mortality, and to provide an overview of cardiac outcomes of glucose-lowering therapy.
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Affiliation(s)
| | - Laura Ernande
- INSERM U955, Université Paris-Est Créteil (UPEC), 94010 Créteil, France; Department of Cardiology, Institut Mondor de Recherche Biomédicale, INSERM U955-Équipe 8, Faculté de Médecine de Créteil, 94010 Créteil, France
| | | | - Ana-Maria Gomez
- Université Paris-Saclay, INSERM, UMR-S 1180, 92296 Châtenay-Malabry, France
| | - Laetitia Pereira
- Université Paris-Saclay, INSERM, UMR-S 1180, 92296 Châtenay-Malabry, France.
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11
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Gallego M, Zayas-Arrabal J, Alquiza A, Apellaniz B, Casis O. Electrical Features of the Diabetic Myocardium. Arrhythmic and Cardiovascular Safety Considerations in Diabetes. Front Pharmacol 2021; 12:687256. [PMID: 34305599 PMCID: PMC8295895 DOI: 10.3389/fphar.2021.687256] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/15/2021] [Indexed: 12/20/2022] Open
Abstract
Diabetes is a chronic metabolic disease characterized by hyperglycemia in the absence of treatment. Among the diabetes-associated complications, cardiovascular disease is the major cause of mortality and morbidity in diabetic patients. Diabetes causes a complex myocardial dysfunction, referred as diabetic cardiomyopathy, which even in the absence of other cardiac risk factors results in abnormal diastolic and systolic function. Besides mechanical abnormalities, altered electrical function is another major feature of the diabetic myocardium. Both type 1 and type 2 diabetic patients often show cardiac electrical remodeling, mainly a prolonged ventricular repolarization visible in the electrocardiogram as a lengthening of the QT interval duration. The underlying mechanisms at the cellular level involve alterations on the expression and activity of several cardiac ion channels and their associated regulatory proteins. Consequent changes in sodium, calcium and potassium currents collectively lead to a delay in repolarization that can increase the risk of developing life-threatening ventricular arrhythmias and sudden death. QT duration correlates strongly with the risk of developing torsade de pointes, a form of ventricular tachycardia that can degenerate into ventricular fibrillation. Therefore, QT prolongation is a qualitative marker of proarrhythmic risk, and analysis of ventricular repolarization is therefore required for the approval of new drugs. To that end, the Thorough QT/QTc analysis evaluates QT interval prolongation to assess potential proarrhythmic effects. In addition, since diabetic patients have a higher risk to die from cardiovascular causes than individuals without diabetes, cardiovascular safety of the new antidiabetic drugs must be carefully evaluated in type 2 diabetic patients. These cardiovascular outcome trials reveal that some glucose-lowering drugs actually reduce cardiovascular risk. The mechanism of cardioprotection might involve a reduction of the risk of developing arrhythmia.
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Affiliation(s)
- Mónica Gallego
- Department of Physiology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
| | - Julián Zayas-Arrabal
- Department of Physiology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
| | - Amaia Alquiza
- Department of Physiology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
| | - Beatriz Apellaniz
- Department of Physiology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
| | - Oscar Casis
- Department of Physiology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
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12
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Al Kury LT, Sydorenko V, Smail MMA, Qureshi MA, Shmygol A, Papandreou D, Singh J, Howarth FC. Calcium signaling in endocardial and epicardial ventricular myocytes from streptozotocin-induced diabetic rats. J Diabetes Investig 2021; 12:493-500. [PMID: 33112506 PMCID: PMC8015823 DOI: 10.1111/jdi.13451] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/08/2020] [Accepted: 10/22/2020] [Indexed: 12/16/2022] Open
Abstract
AIMS/INTRODUCTION Abnormalities in Ca2+ signaling have a key role in hemodynamic dysfunction in diabetic heart. The purpose of this study was to explore the effects of streptozotocin (STZ)-induced diabetes on Ca2+ signaling in epicardial (EPI) and endocardial (ENDO) cells of the left ventricle after 5-6 months of STZ injection. MATERIALS AND METHODS Whole-cell patch clamp was used to measure the L-type Ca2+ channel (LTCC) and Na+ /Ca2+ exchanger currents. Fluorescence photometry techniques were used to measure intracellular free Ca2+ concentration. RESULTS Although the LTCC current was not significantly altered, the amplitude of Ca2+ transients increased significantly in EPI-STZ and ENDO-STZ compared with controls. Time to peak LTCC current, time to peak Ca2+ transient, time to half decay of LTCC current and time to half decay of Ca2+ transients were not significantly changed in EPI-STZ and ENDO-STZ myocytes compared with controls. The Na+ /Ca2+ exchanger current was significantly smaller in EPI-STZ and in ENDO-STZ compared with controls. CONCLUSIONS STZ-induced diabetes resulted in an increase in amplitude of Ca2+ transients in EPI and ENDO myocytes that was independent of the LTCC current. Such an effect can be attributed, at least in part, to the dysfunction of the Na+ /Ca2+ exchanger. Additional studies are warranted to improve our understanding of the regional impact of diabetes on Ca2+ signaling, which will facilitate the discovery of new targeted treatments for diabetic cardiomyopathy.
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Affiliation(s)
- Lina T Al Kury
- Department of Health SciencesCollege of Natural and Health SciencesZayed UniversityAbu DhabiUnited Arab Emirates
| | - Vadym Sydorenko
- Department of Cellular MembranologyBogomoletz Institute of PhysiologyKievUkraine
| | - Manal MA Smail
- Department of PhysiologyCollege of Medicine and Health SciencesUAE UniversityAl AinUnited Arab Emirates
| | - Muhammad A Qureshi
- Department of PhysiologyCollege of Medicine and Health SciencesUAE UniversityAl AinUnited Arab Emirates
| | - Anatoly Shmygol
- Department of PhysiologyCollege of Medicine and Health SciencesUAE UniversityAl AinUnited Arab Emirates
| | - Dimitrios Papandreou
- Department of Health SciencesCollege of Natural and Health SciencesZayed UniversityAbu DhabiUnited Arab Emirates
| | - Jaipaul Singh
- School of Forensic and Applied SciencesUniversity of Central LancashirePrestonUK
| | - Frank Christopher Howarth
- Department of PhysiologyCollege of Medicine and Health SciencesUAE UniversityAl AinUnited Arab Emirates
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13
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Cardiovascular toxicity of PI3Kα inhibitors. Clin Sci (Lond) 2021; 134:2595-2622. [PMID: 33063821 DOI: 10.1042/cs20200302] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 09/27/2020] [Accepted: 09/30/2020] [Indexed: 02/07/2023]
Abstract
The phosphoinositide 3-kinases (PI3Ks) are a family of intracellular lipid kinases that phosphorylate the 3'-hydroxyl group of inositol membrane lipids, resulting in the production of phosphatidylinositol 3,4,5-trisphosphate from phosphatidylinositol 4,5-bisphosphate. This results in downstream effects, including cell growth, proliferation, and migration. The heart expresses three PI3K class I enzyme isoforms (α, β, and γ), and these enzymes play a role in cardiac cellular survival, myocardial hypertrophy, myocardial contractility, excitation, and mechanotransduction. The PI3K pathway is associated with various disease processes but is particularly important to human cancers since many gain-of-function mutations in this pathway occur in various cancers. Despite the development, testing, and regulatory approval of PI3K inhibitors in recent years, there are still significant challenges when creating and utilizing these drugs, including concerns of adverse effects on the heart. There is a growing body of evidence from preclinical studies revealing that PI3Ks play a crucial cardioprotective role, and thus inhibition of this pathway could lead to cardiac dysfunction, electrical remodeling, vascular damage, and ultimately, cardiovascular disease. This review will focus on PI3Kα, including the mechanisms underlying the adverse cardiovascular effects resulting from PI3Kα inhibition and the potential clinical implications of treating patients with these drugs, such as increased arrhythmia burden, biventricular cardiac dysfunction, and impaired recovery from cardiotoxicity. Recommendations for future directions for preclinical and clinical work are made, highlighting the possible role of PI3Kα inhibition in the progression of cancer-related cachexia and female sex and pre-existing comorbidities as independent risk factors for cardiac abnormalities after cancer treatment.
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14
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Ozturk N, Uslu S, Ozdemir S. Diabetes-induced changes in cardiac voltage-gated ion channels. World J Diabetes 2021; 12:1-18. [PMID: 33520105 PMCID: PMC7807254 DOI: 10.4239/wjd.v12.i1.1] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 11/05/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus affects the heart through various mechanisms such as microvascular defects, metabolic abnormalities, autonomic dysfunction and incompatible immune response. Furthermore, it can also cause functional and structural changes in the myocardium by a disease known as diabetic cardiomyopathy (DCM) in the absence of coronary artery disease. As DCM progresses it causes electrical remodeling of the heart, left ventricular dysfunction and heart failure. Electrophysiological changes in the diabetic heart contribute significantly to the incidence of arrhythmias and sudden cardiac death in diabetes mellitus patients. In recent studies, significant changes in repolarizing K+ currents, Na+ currents and L-type Ca2+ currents along with impaired Ca2+ homeostasis and defective contractile function have been identified in the diabetic heart. In addition, insulin levels and other trophic factors change significantly to maintain the ionic channel expression in diabetic patients. There are many diagnostic tools and management options for DCM, but it is difficult to detect its development and to effectively prevent its progress. In this review, diabetes-associated alterations in voltage-sensitive cardiac ion channels are comprehensively assessed to understand their potential role in the pathophysiology and pathogenesis of DCM.
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Affiliation(s)
- Nihal Ozturk
- Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya 07058, Turkey
| | - Serkan Uslu
- Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya 07058, Turkey
| | - Semir Ozdemir
- Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya 07058, Turkey
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15
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Wang H, Wang C, Lu Y, Yan Y, Leng D, Tian S, Zheng D, Wang Z, Bai Y. Metformin Shortens Prolonged QT Interval in Diabetic Mice by Inhibiting L-Type Calcium Current: A Possible Therapeutic Approach. Front Pharmacol 2020; 11:614. [PMID: 32595491 PMCID: PMC7300225 DOI: 10.3389/fphar.2020.00614] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 04/20/2020] [Indexed: 12/11/2022] Open
Abstract
The incidence and mortality of cardiovascular disease in diabetic patients are 2-3 times higher than those in non-diabetic patients. Abnormal function of the L-type calcium channel in myocardial tissue might result in multiple cardiac disorders such as a prolonged QT interval. Therefore, QT prolongation is an independent risk factor of cardiovascular disease in patients with diabetes mellitus. Metformin, a hypoglycemic agent, is widely known to effectively reduce the occurrence of macrovascular diseases. The aim of the present study was to evaluate the effect of metformin on prolonged QT interval and to explore potential ionic mechanisms induced by diabetes. Diabetic mouse models were established with streptozotocin and an electrocardiogram was used to monitor the QT interval after 4 weeks of metformin treatment in each group. Action potential duration (APD) and L-type calcium current (I Ca-L) were detected by patch-clamp in isolated mice ventricular cardiomyocytes and neonatal cardiomyocytes of mice. The expression levels of CACNA1C mRNA and Cav1.2 were measured by real-time PCR, western blot and immunofluorescence. A shortened QT interval was observed after 4 weeks of metformin treatment in diabetic mice. Patch-clamp results revealed that both APD and I Ca-L were shortened in mouse cardiomyocytes. Furthermore, the expression levels of CACNA1C mRNA and Cav1.2 were decreased in the metformin group. The same results were also obtained in cultured neonatal mice cardiomyocytes. Overall, these results verify that metformin could shorten a prolonged QT interval by inhibiting the calcium current, suggesting that metformin may play a role in the electrophysiology underlying diabetic cardiopathy.
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Affiliation(s)
- Hui Wang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Cao Wang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Yuan Lu
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Yan Yan
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Dongjing Leng
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Shanshan Tian
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Dongjie Zheng
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Zhiguo Wang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Yunlong Bai
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine–Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
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16
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Abstract
Diabetes mellitus predisposes affected individuals to a significant spectrum of cardiovascular complications, one of the most debilitating in terms of prognosis is heart failure. Indeed, the increasing global prevalence of diabetes mellitus and an aging population has given rise to an epidemic of diabetes mellitus-induced heart failure. Despite the significant research attention this phenomenon, termed diabetic cardiomyopathy, has received over several decades, understanding of the full spectrum of potential contributing mechanisms, and their relative contribution to this heart failure phenotype in the specific context of diabetes mellitus, has not yet been fully resolved. Key recent preclinical discoveries that comprise the current state-of-the-art understanding of the basic mechanisms of the complex phenotype, that is, the diabetic heart, form the basis of this review. Abnormalities in each of cardiac metabolism, physiological and pathophysiological signaling, and the mitochondrial compartment, in addition to oxidative stress, inflammation, myocardial cell death pathways, and neurohumoral mechanisms, are addressed. Further, the interactions between each of these contributing mechanisms and how they align to the functional, morphological, and structural impairments that characterize the diabetic heart are considered in light of the clinical context: from the disease burden, its current management in the clinic, and where the knowledge gaps remain. The need for continued interrogation of these mechanisms (both known and those yet to be identified) is essential to not only decipher the how and why of diabetes mellitus-induced heart failure but also to facilitate improved inroads into the clinical management of this pervasive clinical challenge.
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Affiliation(s)
- Rebecca H. Ritchie
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Parkville, Victoria 3052, Australia
| | - E. Dale Abel
- Division of Endocrinology and Metabolism, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States
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17
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Noll NA, Lal H, Merryman WD. Mouse Models of Heart Failure with Preserved or Reduced Ejection Fraction. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:1596-1608. [PMID: 32343958 DOI: 10.1016/j.ajpath.2020.04.006] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 04/07/2020] [Accepted: 04/09/2020] [Indexed: 12/12/2022]
Abstract
Heart failure (HF) is a chronic, complex condition with increasing incidence worldwide, necessitating the development of novel therapeutic strategies. This has led to the current clinical strategies, which only treat symptoms of HF without addressing the underlying causes. Multiple animal models have been developed in an attempt to recreate the chronic HF phenotype that arises following a variety of myocardial injuries. Although significant strides have been made in HF research, an understanding of more specific mechanisms will require distinguishing models that resemble HF with preserved ejection fraction (HFpEF) from those with reduced ejection fraction (HFrEF). Therefore, current mouse models of HF need to be re-assessed to determine which of them most closely recapitulate the specific etiology of HF being studied. This will allow for the development of therapies targeted specifically at HFpEF or HFrEF. This review will summarize the commonly used mouse models of HF and discuss which aspect of human HF each model replicates, focusing on whether HFpEF or HFrEF is induced, to allow better investigation into pathophysiological mechanisms and treatment strategies.
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Affiliation(s)
- Natalie A Noll
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Hind Lal
- Department of Medicine, Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama
| | - W David Merryman
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.
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18
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Loss of insulin signaling may contribute to atrial fibrillation and atrial electrical remodeling in type 1 diabetes. Proc Natl Acad Sci U S A 2020; 117:7990-8000. [PMID: 32198206 DOI: 10.1073/pnas.1914853117] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Atrial fibrillation (AF) is prevalent in diabetes mellitus (DM); however, the basis for this is unknown. This study investigated AF susceptibility and atrial electrophysiology in type 1 diabetic Akita mice using in vivo intracardiac electrophysiology, high-resolution optical mapping in atrial preparations, and patch clamping in isolated atrial myocytes. qPCR and western blotting were used to assess ion channel expression. Akita mice were highly susceptible to AF in association with increased P-wave duration and slowed atrial conduction velocity. In a second model of type 1 DM, mice treated with streptozotocin (STZ) showed a similar increase in susceptibility to AF. Chronic insulin treatment reduced susceptibility and duration of AF and shortened P-wave duration in Akita mice. Atrial action potential (AP) morphology was altered in Akita mice due to a reduction in upstroke velocity and increases in AP duration. In Akita mice, atrial Na+ current (INa) and repolarizing K+ current (IK) carried by voltage gated K+ (Kv1.5) channels were reduced. The reduction in INa occurred in association with reduced expression of SCN5a and voltage gated Na+ (NaV1.5) channels as well as a shift in INa activation kinetics. Insulin potently and selectively increased INa in Akita mice without affecting IK Chronic insulin treatment increased INa in association with increased expression of NaV1.5. Acute insulin also increased INa, although to a smaller extent, due to enhanced insulin signaling via phosphatidylinositol 3,4,5-triphosphate (PIP3). Our study reveals a critical, selective role for insulin in regulating atrial INa, which impacts susceptibility to AF in type 1 DM.
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19
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Wan X, Belanger K, Widen SG, Kuyumcu-Martinez MN, Garg NJ. Genes of the cGMP-PKG-Ca 2+ signaling pathway are alternatively spliced in cardiomyopathy: Role of RBFOX2. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165620. [PMID: 31778749 PMCID: PMC6954967 DOI: 10.1016/j.bbadis.2019.165620] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 11/13/2019] [Accepted: 11/21/2019] [Indexed: 12/16/2022]
Abstract
Aberrations in the cGMP-PKG-Ca2+ pathway are implicated in cardiovascular complications of diverse etiologies, though involved molecular mechanisms are not understood. We performed RNA-Seq analysis to profile global changes in gene expression and exon splicing in Chagas disease (ChD) murine myocardium. Ingenuity-Pathway-Analysis of transcriptome dataset identified 26 differentially expressed genes associated with increased mobilization and cellular levels of Ca2+ in ChD hearts. Mixture-of-isoforms and Enrichr KEGG pathway analyses of the RNA-Seq datasets from ChD (this study) and diabetic (previous study) murine hearts identified alternative splicing (AS) in eleven genes (Arhgef10, Atp2b1, Atp2a3, Cacna1c, Itpr1, Mef2a, Mef2d, Pde2a, Plcb1, Plcb4, and Ppp1r12a) of the cGMP-PKG-Ca2+ pathway in diseased hearts. AS of these genes was validated by an exon exclusion-inclusion assay. Further, Arhgef10, Atp2b1, Mef2a, Mef2d, Plcb1, and Ppp1r12a genes consisted RBFOX2 (RNA-binding protein) binding-site clusters, determined by analyzing the RBFOX2 CLIP-Seq dataset. H9c2 rat heart cells transfected with Rbfox2 (vs. scrambled) siRNA confirmed that expression of Rbfox2 is essential for proper exon splicing of genes of the cGMP-PKG-Ca2+ pathway. We conclude that changes in gene expression may influence the Ca2+ mobilization pathway in ChD, and AS impacts the genes involved in cGMP/PKG/Ca2+ signaling pathway in ChD and diabetes. Our findings suggest that ChD patients with diabetes may be at increased risk of cardiomyopathy and heart failure and provide novel ways to restore cGMP-PKG regulated signaling networks via correcting splicing patterns of key factors using oligonucleotide-based therapies for the treatment of cardiovascular complications.
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Affiliation(s)
- Xianxiu Wan
- Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, 77555-1070, TX, United States of America
| | - KarryAnne Belanger
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, 77555, TX, United States of America
| | - Steven G Widen
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, 77555, TX, United States of America
| | - Muge N Kuyumcu-Martinez
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, 77555, TX, United States of America.
| | - Nisha J Garg
- Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, 77555-1070, TX, United States of America; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, 77555, TX, United States of America.
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20
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Al Kury LT. Calcium Homeostasis in Ventricular Myocytes of Diabetic Cardiomyopathy. J Diabetes Res 2020; 2020:1942086. [PMID: 33274235 PMCID: PMC7683117 DOI: 10.1155/2020/1942086] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 10/24/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic disorder commonly characterized by high blood glucose levels, resulting from defects in insulin production or insulin resistance, or both. DM is a leading cause of mortality and morbidity worldwide, with diabetic cardiomyopathy as one of its main complications. It is well established that cardiovascular complications are common in both types of diabetes. Electrical and mechanical problems, resulting in cardiac contractile dysfunction, are considered as the major complications present in diabetic hearts. Inevitably, disturbances in the mechanism(s) of Ca2+ signaling in diabetes have implications for cardiac myocyte contraction. Over the last decade, significant progress has been made in outlining the mechanisms responsible for the diminished cardiac contractile function in diabetes using different animal models of type I diabetes mellitus (TIDM) and type II diabetes mellitus (TIIDM). The aim of this review is to evaluate our current understanding of the disturbances of Ca2+ transport and the role of main cardiac proteins involved in Ca2+ homeostasis in the diabetic rat ventricular cardiomyocytes. Exploring the molecular mechanism(s) of altered Ca2+ signaling in diabetes will provide an insight for the identification of novel therapeutic approaches to improve the heart function in diabetic patients.
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Affiliation(s)
- Lina T. Al Kury
- Department of Health Sciences, College of Natural and Health Sciences, Zayed University, Abu Dhabi 144534, UAE
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21
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Calbiague VM, Vielma AH, Cadiz B, Paquet‐Durand F, Schmachtenberg O. Physiological assessment of high glucose neurotoxicity in mouse and rat retinal explants. J Comp Neurol 2019; 528:989-1002. [DOI: 10.1002/cne.24805] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 09/09/2019] [Accepted: 10/20/2019] [Indexed: 12/31/2022]
Affiliation(s)
- Víctor M. Calbiague
- Centro Interdisciplinario de Neurociencia de Valparaíso (CINV), Facultad de Ciencias Universidad de Valparaíso Valparaíso Chile
- Programa Doctorado en Ciencias, mención Neurociencias Universidad de Valparaíso Valparaíso Chile
| | - Alex H. Vielma
- Centro Interdisciplinario de Neurociencia de Valparaíso (CINV), Facultad de Ciencias Universidad de Valparaíso Valparaíso Chile
| | - Bárbara Cadiz
- Centro Interdisciplinario de Neurociencia de Valparaíso (CINV), Facultad de Ciencias Universidad de Valparaíso Valparaíso Chile
| | - Francois Paquet‐Durand
- Cell Death Mechanism Group Institute for Ophthalmic Research, University of Tübingen Tübingen Germany
| | - Oliver Schmachtenberg
- Centro Interdisciplinario de Neurociencia de Valparaíso (CINV), Facultad de Ciencias Universidad de Valparaíso Valparaíso Chile
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22
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Mechanism of electrical remodeling of atrial myocytes and its influence on susceptibility to atrial fibrillation in diabetic rats. Life Sci 2019; 239:116903. [PMID: 31639397 DOI: 10.1016/j.lfs.2019.116903] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 09/14/2019] [Accepted: 09/22/2019] [Indexed: 02/06/2023]
Abstract
AIMS To explore the atrial electrical remodeling and the susceptibility of atrial fibrillation (AF) in diabetic rats. MATERIALS AND METHODS Zucker diabetic fatty (ZDF) rats were chosen as diabetic animal model, and age-matched non-diabetic littermate Zucker lean (ZL) rats as control. AF susceptibility was determined by electrophysiological examination. The current density of Ito, IKur and ICa-L were detected by whole-cell patch-clamp technique, and ion channel protein expression in atrial tissue and HL-1 cells treated with advanced glycation end products (AGE) was analyzed by western blotting. KEY FINDINGS Diabetic rats had significantly enlarged left atria and evenly thickened ventricular walls, hypertrophied cells and interstitial fibrosis in atrial myocardium, increased AF susceptibility, and prolonged AF duration after atrial burst stimulation. Compared with atrial myocytes isolated from ZL controls, atrial myocytes isolated from ZDF rats had prolonged action potential duration, decreased absolute value of resting membrane potential level and current densities of Ito, IKur and ICa-L. The ion channel protein (Kv4.3, Kv1.5 and Cav1.2) expression in atrium tissue of ZDF rats and HL-1 cells treated with high concentration AGE were significantly down-regulated, compared with controls. SIGNIFICANCE The atrial electrical remodeling induced by hyperglycemia contributed to the increased AF susceptibility in diabetic rats.
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Zhang Y, Welzig CM, Haburcak M, Wang B, Aronovitz M, Blanton RM, Park HJ, Force T, Noujaim S, Galper JB. Targeted disruption of glycogen synthase kinase-3β in cardiomyocytes attenuates cardiac parasympathetic dysfunction in type 1 diabetic Akita mice. PLoS One 2019; 14:e0215213. [PMID: 30978208 PMCID: PMC6461277 DOI: 10.1371/journal.pone.0215213] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 03/25/2019] [Indexed: 11/18/2022] Open
Abstract
Type 1 diabetic Akita mice develop severe cardiac parasympathetic dysfunction that we have previously demonstrated is due at least in part to an abnormality in the response of the end organ to parasympathetic stimulation. Specifically, we had shown that hypoinsulinemia in the diabetic heart results in attenuation of the G-protein coupled inward rectifying K channel (GIRK) which mediates the negative chronotropic response to parasympathetic stimulation due at least in part to decreased expression of the GIRK1 and GIRK4 subunits of the channel. We further demonstrated that the expression of GIRK1 and GIRK4 is under the control of the Sterol Regulatory element Binding Protein (SREBP-1), which is also decreased in response to hypoinsulinemia. Finally, given that hyperactivity of Glycogen Synthase Kinase (GSK)3β, had been demonstrated in the diabetic heart, we demonstrated that treatment of Akita mice with Li+, an inhibitor of GSK3β, increased parasympathetic responsiveness and SREBP-1 levels consistent with the conclusion that GSK3β might regulate IKACh via an effect on SREBP-1. However, inhibitor studies were complicated by lack of specificity for GSK3β. Here we generated an Akita mouse with cardiac specific inducible knockout of GSK3β. Using this mouse, we demonstrate that attenuation of GSK3β expression is associated with an increase in parasympathetic responsiveness measured as an increase in the heart rate response to atropine from 17.3 ± 3.5% (n = 8) prior to 41.2 ± 5.4% (n = 8, P = 0.017), an increase in the duration of carbamylcholine mediated bradycardia from 8.43 ± 1.60 min (n = 7) to 12.71 ± 2.26 min (n = 7, P = 0.028) and an increase in HRV as measured by an increase in the high frequency fraction from 40.78 ± 3.86% to 65.04 ± 5.64 (n = 10, P = 0.005). Furthermore, patch clamp measurements demonstrated a 3-fold increase in acetylcholine stimulated peak IKACh in atrial myocytes from GSK3β deficiency mice compared with control. Finally, western blot analysis of atrial extracts from knockout mice demonstrated increased levels of SREBP-1, GIRK1 and GIRK4 compared with control. Taken together with our prior observations, these data establish a role of increased GSK3β activity in the pathogenesis of parasympathetic dysfunction in type 1 diabetes via the regulation of IKACh and GIRK1/4 expression.
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Affiliation(s)
- Yali Zhang
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America
- * E-mail: (YZ); (JBG)
| | - Charles M. Welzig
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America
- Departments of Neurology and Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Marian Haburcak
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America
| | - Bo Wang
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America
| | - Mark Aronovitz
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America
| | - Robert M. Blanton
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America
- Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | - Ho-Jin Park
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America
| | - Thomas Force
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Sami Noujaim
- Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, United States of America
| | - Jonas B. Galper
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America
- Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, United States of America
- * E-mail: (YZ); (JBG)
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Empagliflozin Attenuates Myocardial Sodium and Calcium Dysregulation and Reverses Cardiac Remodeling in Streptozotocin-Induced Diabetic Rats. Int J Mol Sci 2019; 20:ijms20071680. [PMID: 30987285 PMCID: PMC6479313 DOI: 10.3390/ijms20071680] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 03/30/2019] [Accepted: 04/02/2019] [Indexed: 12/18/2022] Open
Abstract
Diabetes mellitus (DM) has significant effects on cardiac calcium (Ca2+) and sodium (Na+) regulation. Clinical studies have shown that empagliflozin (Jardiance™) has cardiovascular benefits, however the mechanisms have not been fully elucidated. This study aimed to investigate whether empagliflozin modulates cardiac electrical activity as well as Ca2+/Na+ homeostasis in DM cardiomyopathy. Electrocardiography, echocardiography, whole-cell patch-clamp, confocal microscopic examinations, and Western blot, were performed in the ventricular myocytes of control and streptozotocin-induced DM rats, with or without empagliflozin (10 mg/kg for 4 weeks). The results showed that the control and empagliflozin-treated DM rats had smaller left ventricular end-diastolic diameters and shorter QT intervals than the DM rats. In addition, the prolonged action potential duration in the DM rats was attenuated in the empagliflozin-treated DM rats. Moreover, the DM rats had smaller sarcoplasmic reticular Ca2+ contents, intracellular Ca2+ transients, L-type Ca2+, reverse mode Na+-Ca2+exchanger currents, lower protein expressions of sarcoplasmic reticulum ATPase, ryanodine receptor 2 (RyR2), but higher protein expressions of phosphorylated RyR2 at serine 2808 than the control and empagliflozin-treated DM rats. The incidence and frequency of Ca2+ sparks, cytosolic and mitochondrial reactive oxygen species, and late Na+ current and Na+/hydrogen-exchanger currents were greater in the DM rats than in the control and empagliflozin-treated DM rats. Empagliflozin significantly changed Ca2+ regulation, late Na+ and Na+/hydrogen-exchanger currents and electrophysiological characteristics in DM cardiomyopathy, which may contribute to its cardioprotective benefits in DM patients.
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Gutiérrez A, Contreras C, Sánchez A, Prieto D. Role of Phosphatidylinositol 3-Kinase (PI3K), Mitogen-Activated Protein Kinase (MAPK), and Protein Kinase C (PKC) in Calcium Signaling Pathways Linked to the α 1-Adrenoceptor in Resistance Arteries. Front Physiol 2019; 10:55. [PMID: 30787881 PMCID: PMC6372516 DOI: 10.3389/fphys.2019.00055] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 01/17/2019] [Indexed: 01/07/2023] Open
Abstract
Insulin resistance plays a key role in the pathogenesis of type 2 diabetes and is also related to other health problems like obesity, hypertension, and metabolic syndrome. Imbalance between insulin vascular actions via the phosphatidylinositol 3-Kinase (PI3K) and the mitogen activated protein kinase (MAPK) signaling pathways during insulin resistant states results in impaired endothelial PI3K/eNOS- and augmented MAPK/endothelin 1 pathways leading to endothelial dysfunction and abnormal vasoconstriction. The role of PI3K, MAPK, and protein kinase C (PKC) in Ca2+ handling of resistance arteries involved in blood pressure regulation is poorly understood. Therefore, we assessed here whether PI3K, MAPK, and PKC play a role in the Ca2+ signaling pathways linked to adrenergic vasoconstriction in resistance arteries. Simultaneous measurements of intracellular calcium concentration ([Ca2+]i) in vascular smooth muscle (VSM) and tension were performed in endothelium-denuded branches of mesenteric arteries from Wistar rats mounted in a microvascular myographs. Responses to CaCl2 were assessed in arteries activated with phenylephrine (PE) and kept in Ca2+-free solution, in the absence and presence of the selective antagonist of L-type Ca2+ channels nifedipine, cyclopiazonic acid (CPA) to block sarcoplasmic reticulum (SR) intracellular Ca2+ release or specific inhibitors of PI3K, ERK-MAPK, or PKC. Activation of α1-adrenoceptors with PE stimulated both intracellular Ca2+ mobilization and Ca2+ entry along with contraction in resistance arteries. Both [Ca2+]i and contractile responses were inhibited by nifedipine while CPA abolished intracellular Ca2+ mobilization and modestly reduced Ca2+ entry suggesting that α1-adrenergic vasoconstriction is largely dependent Ca2+ influx through L-type Ca2+ channel and to a lesser extent through store-operated Ca2+ channels. Inhibition of ERK-MAPK did not alter intracellular Ca2+ mobilization but largely reduced L-type Ca2+ entry elicited by PE without altering vasoconstriction. The PI3K blocker LY-294002 moderately reduced intracellular Ca2+ release, Ca2+ entry and contraction induced by the α1-adrenoceptor agonist, while PKC inhibition decreased PE-elicited Ca2+ entry and to a lesser extent contraction without affecting intracellular Ca2+ mobilization. Under conditions of ryanodine receptor (RyR) blockade to inhibit Ca2+-induced Ca2+-release (CICR), inhibitors of PI3K, ERK-MAPK, or PKC significantly reduced [Ca2+]i increases but not contraction elicited by high K+ depolarization suggesting an activation of L-type Ca2+ entry in VSM independent of RyR. In summary, our results demonstrate that PI3K, ERK-MAPK, and PKC regulate Ca2+ handling coupled to the α1-adrenoceptor in VSM of resistance arteries and related to both contractile and non-contractile functions. These kinases represent potential pharmacological targets in pathologies associated to vascular dysfunction and abnormal Ca2+ handling such as obesity, hypertension and diabetes mellitus, in which these signaling pathways are profoundly impaired.
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Affiliation(s)
- Alejandro Gutiérrez
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain
| | - Cristina Contreras
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain
| | - Ana Sánchez
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain
| | - Dolores Prieto
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain
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Maffei A, Lembo G, Carnevale D. PI3Kinases in Diabetes Mellitus and Its Related Complications. Int J Mol Sci 2018; 19:ijms19124098. [PMID: 30567315 PMCID: PMC6321267 DOI: 10.3390/ijms19124098] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 12/13/2018] [Accepted: 12/15/2018] [Indexed: 02/07/2023] Open
Abstract
Recent studies have shown that phosphoinositide 3-kinases (PI3Ks) have become the target of many pharmacological treatments, both in clinical trials and in clinical practice. PI3Ks play an important role in glucose regulation, and this suggests their possible involvement in the onset of diabetes mellitus. In this review, we gather our knowledge regarding the effects of PI3K isoforms on glucose regulation in several organs and on the most clinically-relevant complications of diabetes mellitus, such as cardiomyopathy, vasculopathy, nephropathy, and neurological disease. For instance, PI3K α has been proven to be protective against diabetes-induced heart failure, while PI3K γ inhibition is protective against the disease onset. In vessels, PI3K γ can generate oxidative stress, while PI3K β inhibition is anti-thrombotic. Finally, we describe the role of PI3Ks in Alzheimer’s disease and ADHD, discussing the relevance for diabetic patients. Given the high prevalence of diabetes mellitus, the multiple effects here described should be taken into account for the development and validation of drugs acting on PI3Ks.
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Affiliation(s)
- Angelo Maffei
- Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, 86077 Pozzilli, Italy.
| | - Giuseppe Lembo
- Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, 86077 Pozzilli, Italy.
- Department of Molecular Medicine, "Sapienza" University of Rome, 00161 Rome, Italy.
| | - Daniela Carnevale
- Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, 86077 Pozzilli, Italy.
- Department of Molecular Medicine, "Sapienza" University of Rome, 00161 Rome, Italy.
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Hamilton S, Terentyev D. Proarrhythmic Remodeling of Calcium Homeostasis in Cardiac Disease; Implications for Diabetes and Obesity. Front Physiol 2018. [PMID: 30425651 DOI: 10.3389/fphys.2018.01517, 10.3389/fpls.2018.01517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
A rapid growth in the incidence of diabetes and obesity has transpired to a major heath issue and economic burden in the postindustrial world, with more than 29 million patients affected in the United States alone. Cardiovascular defects have been established as the leading cause of mortality and morbidity of diabetic patients. Over the last decade, significant progress has been made in delineating mechanisms responsible for the diminished cardiac contractile function and enhanced propensity for malignant cardiac arrhythmias characteristic of diabetic disease. Rhythmic cardiac contractility relies upon the precise interplay between several cellular Ca2+ transport protein complexes including plasmalemmal L-type Ca2+ channels (LTCC), Na+-Ca2+ exchanger (NCX1), Sarco/endoplasmic Reticulum (SR) Ca2+-ATPase (SERCa2a) and ryanodine receptors (RyR2s), the SR Ca2+ release channels. Here we provide an overview of changes in Ca2+ homeostasis in diabetic ventricular myocytes and discuss the therapeutic potential of targeting Ca2+ handling proteins in the prevention of diabetes-associated cardiomyopathy and arrhythmogenesis.
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Affiliation(s)
- Shanna Hamilton
- Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, United States.,Cardiovascular Research Center, Rhode Island Hospital, Providence, RI, United States
| | - Dmitry Terentyev
- Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, United States.,Cardiovascular Research Center, Rhode Island Hospital, Providence, RI, United States
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28
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Hamilton S, Terentyev D. Proarrhythmic Remodeling of Calcium Homeostasis in Cardiac Disease; Implications for Diabetes and Obesity. Front Physiol 2018; 9:1517. [PMID: 30425651 PMCID: PMC6218530 DOI: 10.3389/fphys.2018.01517] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 10/09/2018] [Indexed: 12/28/2022] Open
Abstract
A rapid growth in the incidence of diabetes and obesity has transpired to a major heath issue and economic burden in the postindustrial world, with more than 29 million patients affected in the United States alone. Cardiovascular defects have been established as the leading cause of mortality and morbidity of diabetic patients. Over the last decade, significant progress has been made in delineating mechanisms responsible for the diminished cardiac contractile function and enhanced propensity for malignant cardiac arrhythmias characteristic of diabetic disease. Rhythmic cardiac contractility relies upon the precise interplay between several cellular Ca2+ transport protein complexes including plasmalemmal L-type Ca2+ channels (LTCC), Na+-Ca2+ exchanger (NCX1), Sarco/endoplasmic Reticulum (SR) Ca2+-ATPase (SERCa2a) and ryanodine receptors (RyR2s), the SR Ca2+ release channels. Here we provide an overview of changes in Ca2+ homeostasis in diabetic ventricular myocytes and discuss the therapeutic potential of targeting Ca2+ handling proteins in the prevention of diabetes-associated cardiomyopathy and arrhythmogenesis.
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Affiliation(s)
- Shanna Hamilton
- Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, United States.,Cardiovascular Research Center, Rhode Island Hospital, Providence, RI, United States
| | - Dmitry Terentyev
- Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, United States.,Cardiovascular Research Center, Rhode Island Hospital, Providence, RI, United States
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29
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Al Kury L, Smail M, Qureshi MA, Sydorenko V, Shmygol A, Oz M, Singh J, Howarth FC. Calcium Signaling in the Ventricular Myocardium of the Goto-Kakizaki Type 2 Diabetic Rat. J Diabetes Res 2018; 2018:2974304. [PMID: 29850600 PMCID: PMC5914098 DOI: 10.1155/2018/2974304] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 01/16/2018] [Accepted: 03/08/2018] [Indexed: 12/18/2022] Open
Abstract
The association between diabetes mellitus (DM) and high mortality linked to cardiovascular disease (CVD) is a major concern worldwide. Clinical and preclinical studies have demonstrated a variety of diastolic and systolic dysfunctions in patients with type 2 diabetes mellitus (T2DM) with the severity of abnormalities depending on the patients' age and duration of diabetes. The cellular basis of hemodynamic dysfunction in a type 2 diabetic heart is still not well understood. The aim of this review is to evaluate our current understanding of contractile dysfunction and disturbances of Ca2+ transport in the Goto-Kakizaki (GK) diabetic rat heart. The GK rat is a widely used nonobese, nonhypertensive genetic model of T2DM which is characterized by insulin resistance, elevated blood glucose, alterations in blood lipid profile, and cardiac dysfunction.
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Affiliation(s)
- L. Al Kury
- College of Natural and Health Sciences, Zayed University, Abu Dhabi, UAE
| | - M. Smail
- Department of Physiology, College of Medicine & Health Sciences, UAE University, Al Ain, UAE
| | - M. A. Qureshi
- Department of Physiology, College of Medicine & Health Sciences, UAE University, Al Ain, UAE
| | - V. Sydorenko
- Department of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, Ukraine
| | - A. Shmygol
- Department of Physiology, College of Medicine & Health Sciences, UAE University, Al Ain, UAE
| | - M. Oz
- Department of Basic Medical Sciences, College of Medicine, Qatar University, Doha, Qatar
| | - J. Singh
- School of Forensic & Applied Sciences, University of Central Lancashire, Preston, UK
| | - F. C. Howarth
- Department of Physiology, College of Medicine & Health Sciences, UAE University, Al Ain, UAE
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30
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Russell J, Du Toit EF, Peart JN, Patel HH, Headrick JP. Myocyte membrane and microdomain modifications in diabetes: determinants of ischemic tolerance and cardioprotection. Cardiovasc Diabetol 2017; 16:155. [PMID: 29202762 PMCID: PMC5716308 DOI: 10.1186/s12933-017-0638-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 11/22/2017] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular disease, predominantly ischemic heart disease (IHD), is the leading cause of death in diabetes mellitus (DM). In addition to eliciting cardiomyopathy, DM induces a ‘wicked triumvirate’: (i) increasing the risk and incidence of IHD and myocardial ischemia; (ii) decreasing myocardial tolerance to ischemia–reperfusion (I–R) injury; and (iii) inhibiting or eliminating responses to cardioprotective stimuli. Changes in ischemic tolerance and cardioprotective signaling may contribute to substantially higher mortality and morbidity following ischemic insult in DM patients. Among the diverse mechanisms implicated in diabetic impairment of ischemic tolerance and cardioprotection, changes in sarcolemmal makeup may play an overarching role and are considered in detail in the current review. Observations predominantly in animal models reveal DM-dependent changes in membrane lipid composition (cholesterol and triglyceride accumulation, fatty acid saturation vs. reduced desaturation, phospholipid remodeling) that contribute to modulation of caveolar domains, gap junctions and T-tubules. These modifications influence sarcolemmal biophysical properties, receptor and phospholipid signaling, ion channel and transporter functions, contributing to contractile and electrophysiological dysfunction, cardiomyopathy, ischemic intolerance and suppression of protective signaling. A better understanding of these sarcolemmal abnormalities in types I and II DM (T1DM, T2DM) can inform approaches to limiting cardiomyopathy, associated IHD and their consequences. Key knowledge gaps include details of sarcolemmal changes in models of T2DM, temporal patterns of lipid, microdomain and T-tubule changes during disease development, and the precise impacts of these diverse sarcolemmal modifications. Importantly, exercise, dietary, pharmacological and gene approaches have potential for improving sarcolemmal makeup, and thus myocyte function and stress-resistance in this ubiquitous metabolic disorder.
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Affiliation(s)
- Jake Russell
- Menzies Health Institute Queensland, Griffith University, Southport, QLD, Australia
| | - Eugene F Du Toit
- Menzies Health Institute Queensland, Griffith University, Southport, QLD, Australia
| | - Jason N Peart
- Menzies Health Institute Queensland, Griffith University, Southport, QLD, Australia
| | - Hemal H Patel
- VA San Diego Healthcare System and Department of Anesthesiology, University of California San Diego, San Diego, USA
| | - John P Headrick
- Menzies Health Institute Queensland, Griffith University, Southport, QLD, Australia. .,School of Medical Science, Griffith University, Southport, QLD, 4217, Australia.
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Abstract
Receptors that activate the heterotrimeric G protein Gαq are thought to play a role in the development of heart failure. Dysregulation of autophagy occurs in some pathological cardiac conditions including heart failure, but whether Gαq is involved in this process is unknown. We used a cardiomyocyte-specific transgenic mouse model of inducible Gαq activation (termed GαqQ209L) to address this question. After 7 days of Gαq activation, GαqQ209L hearts contained more autophagic vacuoles than wild type hearts. Increased levels of proteins involved in autophagy, especially p62 and LC3-II, were also seen. LysoTracker staining and western blotting showed that the number and size of lysosomes and lysosomal protein levels were increased in GαqQ209L hearts, indicating enhanced lysosomal degradation activity. Importantly, an autophagic flux assay measuring LC3-II turnover in isolated adult cardiomyocytes indicated that autophagic activity is enhanced in GαqQ209L hearts. GαqQ209L hearts exhibited elevated levels of the autophagy initiation complex, which contains the Class III phosphoinositide 3-kinase Vps34. As a consequence, Vps34 activity and phosphatidylinositol 3-phosphate levels were higher in GαqQ209L hearts than wild type hearts, thus accounting for the higher abundance of autophagic vacuoles. These results indicate that an increase in autophagy is an early response to Gαq activation in the heart.
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Abstract
Receptor signaling relays on intracellular events amplified by secondary and tertiary messenger molecules. In cardiomyocytes and smooth muscle cells, cyclic AMP (cAMP) and subsequent calcium (Ca2+) fluxes are the best characterized receptor-regulated signaling events. However, most of receptors able to modify contractility and other intracellular responses signal through a variety of other messengers, and whether these signaling events are interconnected has long remained unclear. For example, the PI3K (phosphoinositide 3-kinase) pathway connected to the production of the lipid second messenger PIP3/PtdIns(3,4,5)P3 (phosphatidylinositol (3,4,5)-trisphosphate) is potentially involved in metabolic regulation, activation of hypertrophy, and survival pathways. Recent studies, highlighted in this review, started to interconnect PI3K pathway activation to Ca2+ signaling. This interdependency, by balancing contractility with metabolic control, is crucial for cells of the cardiovascular system and is emerging to play key roles in disease development. Better understanding of the interplay between Ca2+ and PI3K signaling is, thus, expected to provide new ground for therapeutic intervention. This review explores the emerging molecular mechanisms linking Ca2+ and PI3K signaling in health and disease.
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Affiliation(s)
- Alessandra Ghigo
- From the Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Italy (A.G., M. Li, E.H.); and INSERM U1048, I2MC and Université Toulouse III, France (M. Laffargue)
| | - Muriel Laffargue
- From the Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Italy (A.G., M. Li, E.H.); and INSERM U1048, I2MC and Université Toulouse III, France (M. Laffargue)
| | - Mingchuan Li
- From the Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Italy (A.G., M. Li, E.H.); and INSERM U1048, I2MC and Université Toulouse III, France (M. Laffargue)
| | - Emilio Hirsch
- From the Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Italy (A.G., M. Li, E.H.); and INSERM U1048, I2MC and Université Toulouse III, France (M. Laffargue).
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Nelson RK, Ya-Ping J, Gadbery J, Abedeen D, Sampson N, Lin RZ, Frohman MA. Phospholipase D2 loss results in increased blood pressure via inhibition of the endothelial nitric oxide synthase pathway. Sci Rep 2017; 7:9112. [PMID: 28831159 PMCID: PMC5567230 DOI: 10.1038/s41598-017-09852-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 07/14/2017] [Indexed: 11/10/2022] Open
Abstract
The Phospholipase D (PLD) superfamily is linked to neurological disease, cancer, and fertility, and a recent report correlated a potential loss-of-function PLD2 polymorphism with hypotension. Surprisingly, PLD2 -/- mice exhibit elevated blood pressure accompanied by associated changes in cardiac performance and molecular markers, but do not have findings consistent with the metabolic syndrome. Instead, expression of endothelial nitric oxide synthase (eNOS), which generates the potent vasodilator nitric oxide (NO), is decreased. An eNOS inhibitor phenocopied PLD2 loss and had no further effect on PLD2 -/- mice, confirming the functional relationship. Using a human endothelial cell line, PLD2 loss of function was shown to lower intracellular free cholesterol, causing upregulation of HMG Co-A reductase, the rate-limiting enzyme in cholesterol synthesis. HMG Co-A reductase negatively regulates eNOS, and the PLD2-deficiency phenotype of decreased eNOS expression and activity could be rescued by cholesterol supplementation and HMG Co-A reductase inhibition. Together, these findings identify a novel pathway through which the lipid signaling enzyme PLD2 regulates blood pressure, creating implications for on-going therapeutic development of PLD small molecule inhibitors. Finally, we show that the human PLD2 polymorphism does not trigger eNOS loss, but rather creates another effect, suggesting altered functioning for the allele.
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Affiliation(s)
- Rochelle K Nelson
- The Graduate Program in Physiology & Biophysics, Stony Brook University, New York, USA
| | - Jiang Ya-Ping
- Department of Physiology & Biophysics, Stony Brook University, New York, USA
| | - John Gadbery
- Biochemistry and Structural Biology, Stony Brook University, New York, USA
| | - Danya Abedeen
- The Undergraduate Program in Biochemistry, Stony Brook University, New York, USA
| | - Nicole Sampson
- Biochemistry and Structural Biology, Stony Brook University, New York, USA
- Department of Chemistry, Stony Brook University, New York, USA
| | - Richard Z Lin
- Department of Physiology & Biophysics, Stony Brook University, New York, USA
- Medical Service, Northport Veterans Affairs Medical Center, Northport, NY, USA
| | - Michael A Frohman
- Department of Pharmacological Sciences, Stony Brook University, New York, USA.
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Howarth FC, Parekh K, Jayaprakash P, Inbaraj ES, Oz M, Dobrzynski H, Adrian TE. Altered profile of mRNA expression in atrioventricular node of streptozotocin‑induced diabetic rats. Mol Med Rep 2017; 16:3720-3730. [PMID: 28731153 PMCID: PMC5646948 DOI: 10.3892/mmr.2017.7038] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 07/11/2017] [Indexed: 02/07/2023] Open
Abstract
Prolonged action potential duration, reduced action potential firing rate, upstroke velocity and rate of diastolic depolarization have been demonstrated in atrioventricular node (AVN) cells from streptozotocin (STZ)-induced diabetic rats. To further clarify the molecular basis of these electrical disturbances, the mRNA profiles encoding a variety of proteins associated with the generation and conduction of electrical activity in the AVN, were evaluated in the STZ-induced diabetic rat heart. Expression of mRNA was measured in AVN biopsies using reverse transcription-quantitative polymerase chain reaction techniques. Notable differences in mRNA expression included upregulation of genes encoding membrane and intracellular Ca2+ transport, including solute carrier family 8 member A1, transient receptor potential channel 1, ryanodine receptor 2/3, hyperpolarization-activated cyclic-nucleotide 2 and 3, calcium channel voltage-dependent, β2 subunit and sodium channels 3a, 4a, 7a and 3b. In addition to this, potassium channels potassium voltage-gated channel subfamily A member 4, potassium channel calcium activated intermediate/small conductance subfamily N α member 2, potassium voltage-gated channel subfamily J members 3, 5, and 11, potassium channel subfamily K members 1, 2, 3 and natriuretic peptide B (BNP) were upregulated in AVN of STZ heart, compared with controls. Alterations in gene expression were associated with upregulation of various proteins including the inwardly rectifying, potassium channel Kir3.4, NCX1 and BNP. The present study demonstrated notable differences in the profile of mRNA encoding proteins associated with the generation, conduction and regulation of electrical signals in the AVN of the STZ-induced diabetic rat heart. These data will provide a basis for a substantial range of future studies to investigate whether variations in mRNA translate into alterations in electrophysiological function.
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Affiliation(s)
- Frank Christopher Howarth
- Department of Physiology, College of Medicine and Health Sciences, UAE University, Al Ain 17666, United Arab Emirates
| | - Khatija Parekh
- Department of Physiology, College of Medicine and Health Sciences, UAE University, Al Ain 17666, United Arab Emirates
| | - Petrilla Jayaprakash
- Department of Physiology, College of Medicine and Health Sciences, UAE University, Al Ain 17666, United Arab Emirates
| | - Edward Samuel Inbaraj
- Department of Physiology, College of Medicine and Health Sciences, UAE University, Al Ain 17666, United Arab Emirates
| | - Murat Oz
- Department of Pharmacology, College of Medicine and Health Sciences, UAE University, Al Ain 17666, United Arab Emirates
| | - Halina Dobrzynski
- Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, United Kingdom
| | - Thomas Edward Adrian
- Department of Physiology, College of Medicine and Health Sciences, UAE University, Al Ain 17666, United Arab Emirates
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Lu Z, Lense L, Sharma M, Shah A, Luu Y, Cardinal L, Faro J, Kaell A. Prevalence of QT prolongation and associated LVEF changes in diabetic patients over a four-year retrospective time period. J Community Hosp Intern Med Perspect 2017. [PMID: 28638571 PMCID: PMC5473188 DOI: 10.1080/20009666.2017.1320203] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Aim: To evaluate the prevalence and longitudinal changes of prolonged QTc in DM patients admitted to our community hospital, and to determine, if any, its correlation with changes of left ventricular ejection fraction (LVEF). Methods: A retrospective chart review of patients with Type 1 (T1DM) and Type 2 (T2DM) with at least two admissions during a four-year period was performed to identify QTc interval, and LVEF, as measured on transthoracic echocardiogram. Changes in QTc and LVEF between patient hospital admissions were compared. Results: A prolonged QTc interval was found in 66.7% (n = 24) of type 1 and 51.3% (n = 154) type 2 diabetic patients. The QTc interval is progressively increased in both type 1 and type 2 diabetes during follow-up, although it did not reach statistical significance. A total of 62% patients (23 out 37 patients) had a reduction of LVEF during follow-up. Conclusion and Discussion: High prevalence of QTc prolongation was confirmed in hospitalized patients with in both T1DM and T2DM. Significant reduction of LVEF correlated with QTc prolongation over a mean of 17.3 months in T2DM patients, and may have implications for interventions. Abbreviations CHF: Congestive heart failure LVEF: Left ventricular ejection fraction
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Affiliation(s)
- Zhongju Lu
- Department of Internal Medicine, John T. Mather Memorial Hospital, Port Jefferson, NY, USA
| | - Lloyd Lense
- Division of Cardiology, Stony Brook University Hospital, Stony Brook, NY, USA
| | - Mohit Sharma
- Department of Internal Medicine, John T. Mather Memorial Hospital, Port Jefferson, NY, USA
| | - Ankit Shah
- Department of Internal Medicine, John T. Mather Memorial Hospital, Port Jefferson, NY, USA
| | - Ying Luu
- Department of Internal Medicine, John T. Mather Memorial Hospital, Port Jefferson, NY, USA
| | - Lucien Cardinal
- Department of Internal Medicine, John T. Mather Memorial Hospital, Port Jefferson, NY, USA
| | - Joan Faro
- Department of Internal Medicine, John T. Mather Memorial Hospital, Port Jefferson, NY, USA
| | - Alan Kaell
- Department of Internal Medicine, John T. Mather Memorial Hospital, Port Jefferson, NY, USA
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Ritchie RH, Zerenturk EJ, Prakoso D, Calkin AC. Lipid metabolism and its implications for type 1 diabetes-associated cardiomyopathy. J Mol Endocrinol 2017; 58:R225-R240. [PMID: 28373293 DOI: 10.1530/jme-16-0249] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 04/03/2017] [Indexed: 12/13/2022]
Abstract
Diabetic cardiomyopathy was first defined over four decades ago. It was observed in small post-mortem studies of diabetic patients who suffered from concomitant heart failure despite the absence of hypertension, coronary disease or other likely causal factors, as well as in large population studies such as the Framingham Heart Study. Subsequent studies continue to demonstrate an increased incidence of heart failure in the setting of diabetes independent of established risk factors, suggesting direct effects of diabetes on the myocardium. Impairments in glucose metabolism and handling receive the majority of the blame. The role of concomitant impairments in lipid handling, particularly at the level of the myocardium, has however received much less attention. Cardiac lipid accumulation commonly occurs in the setting of type 2 diabetes and has been suggested to play a direct causal role in the development of cardiomyopathy and heart failure in a process termed as cardiac lipotoxicity. Excess lipids promote numerous pathological processes linked to the development of cardiomyopathy, including mitochondrial dysfunction and inflammation. Although somewhat underappreciated, cardiac lipotoxicity also occurs in the setting of type 1 diabetes. This phenomenon is, however, largely understudied in comparison to hyperglycaemia, which has been widely studied in this context. The current review addresses the changes in lipid metabolism occurring in the type 1 diabetic heart and how they are implicated in disease progression. Furthermore, the pathological pathways linked to cardiac lipotoxicity are discussed. Finally, we consider novel approaches for modulating lipid metabolism as a cardioprotective mechanism against cardiomyopathy and heart failure.
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Affiliation(s)
- Rebecca H Ritchie
- Heart Failure PharmacologyBaker Heart & Diabetes Institute, Melbourne, Victoria, Australia
- Central Clinical SchoolMonash University, Melbourne, Victoria, Australia
| | - Eser J Zerenturk
- Lipid Metabolism & Cardiometabolic Disease LaboratoryBaker Heart & Diabetes Institute, Melbourne, Victoria, Australia
| | - Darnel Prakoso
- Heart Failure PharmacologyBaker Heart & Diabetes Institute, Melbourne, Victoria, Australia
- School of BiosciencesThe University of Melbourne, Parkville, Victoria, Australia
| | - Anna C Calkin
- Central Clinical SchoolMonash University, Melbourne, Victoria, Australia
- Lipid Metabolism & Cardiometabolic Disease LaboratoryBaker Heart & Diabetes Institute, Melbourne, Victoria, Australia
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Rusconi F, Ceriotti P, Miragoli M, Carullo P, Salvarani N, Rocchetti M, Di Pasquale E, Rossi S, Tessari M, Caprari S, Cazade M, Kunderfranco P, Chemin J, Bang ML, Polticelli F, Zaza A, Faggian G, Condorelli G, Catalucci D. Peptidomimetic Targeting of Cavβ2 Overcomes Dysregulation of the L-Type Calcium Channel Density and Recovers Cardiac Function. Circulation 2016; 134:534-46. [PMID: 27486162 DOI: 10.1161/circulationaha.116.021347] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 06/27/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND L-type calcium channels (LTCCs) play important roles in regulating cardiomyocyte physiology, which is governed by appropriate LTCC trafficking to and density at the cell surface. Factors influencing the expression, half-life, subcellular trafficking, and gating of LTCCs are therefore critically involved in conditions of cardiac physiology and disease. METHODS Yeast 2-hybrid screenings, biochemical and molecular evaluations, protein interaction assays, fluorescence microscopy, structural molecular modeling, and functional studies were used to investigate the molecular mechanisms through which the LTCC Cavβ2 chaperone regulates channel density at the plasma membrane. RESULTS On the basis of our previous results, we found a direct linear correlation between the total amount of the LTCC pore-forming Cavα1.2 and the Akt-dependent phosphorylation status of Cavβ2 both in a mouse model of diabetic cardiac disease and in 6 diabetic and 7 nondiabetic cardiomyopathy patients with aortic stenosis undergoing aortic valve replacement. Mechanistically, we demonstrate that a conformational change in Cavβ2 triggered by Akt phosphorylation increases LTCC density at the cardiac plasma membrane, and thus the inward calcium current, through a complex pathway involving reduction of Cavα1.2 retrograde trafficking and protein degradation through the prevention of dynamin-mediated LTCC endocytosis; promotion of Cavα1.2 anterograde trafficking by blocking Kir/Gem-dependent sequestration of Cavβ2, thus facilitating the chaperoning of Cavα1.2; and promotion of Cavα1.2 transcription by the prevention of Kir/Gem-mediated shuttling of Cavβ2 to the nucleus, where it limits the transcription of Cavα1.2 through recruitment of the heterochromatin protein 1γ epigenetic repressor to the Cacna1c promoter. On the basis of this mechanism, we developed a novel mimetic peptide that, through targeting of Cavβ2, corrects LTCC life-cycle alterations, facilitating the proper function of cardiac cells. Delivery of mimetic peptide into a mouse model of diabetic cardiac disease associated with LTCC abnormalities restored impaired calcium balance and recovered cardiac function. CONCLUSIONS We have uncovered novel mechanisms modulating LTCC trafficking and life cycle and provide proof of concept for the use of Cavβ2 mimetic peptide as a novel therapeutic tool for the improvement of cardiac conditions correlated with alterations in LTCC levels and function.
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Affiliation(s)
- Francesca Rusconi
- From Humanitas Clinical and Research Center, Rozzano, Milan, Italy (F.R., P. Ceriotti, M.M., P. Carullo, N.S., E.D.P., P.K., M.-L.B., G.C., D.C.); Institute of Genetic and Biomedical Research UOS Milan National Research Council, Milan, Italy (F.R., P. Carullo, N.S., E.D.P., M.-L.B., D.C.); Department of Biotechnologies and Biosciences, University of Milan-Bicocca, Milan, Italy (M.R., A.Z.); Departments of Life Sciences (S.R.) and Clinical and Experimental Medicine (M.M.), University of Parma, Parma, Italy; University Hospital of Verona, Division of Cardiac Surgery, Verona, Italy (M.T., G.F.); Department of Sciences, University of Roma Tre, Rome, Italy (S.C., F.P.); University of Montpellier, CNRS UMR 5203, INSERM, Department of Neuroscience, Institute for Functional Genomics, LabEx Ion Channel Science and Therapeutics, Montpellier, France (M.C., J.C.); and National Institute of Nuclear Physics, Rome Tre Section, Rome, Italy (F.P.)
| | - Paola Ceriotti
- From Humanitas Clinical and Research Center, Rozzano, Milan, Italy (F.R., P. Ceriotti, M.M., P. Carullo, N.S., E.D.P., P.K., M.-L.B., G.C., D.C.); Institute of Genetic and Biomedical Research UOS Milan National Research Council, Milan, Italy (F.R., P. Carullo, N.S., E.D.P., M.-L.B., D.C.); Department of Biotechnologies and Biosciences, University of Milan-Bicocca, Milan, Italy (M.R., A.Z.); Departments of Life Sciences (S.R.) and Clinical and Experimental Medicine (M.M.), University of Parma, Parma, Italy; University Hospital of Verona, Division of Cardiac Surgery, Verona, Italy (M.T., G.F.); Department of Sciences, University of Roma Tre, Rome, Italy (S.C., F.P.); University of Montpellier, CNRS UMR 5203, INSERM, Department of Neuroscience, Institute for Functional Genomics, LabEx Ion Channel Science and Therapeutics, Montpellier, France (M.C., J.C.); and National Institute of Nuclear Physics, Rome Tre Section, Rome, Italy (F.P.)
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Meo M, Meste O, Signore S, Sorrentino A, Cannata A, Zhou Y, Matsuda A, Luciani M, Kannappan R, Goichberg P, Leri A, Anversa P, Rota M. Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm. J Am Heart Assoc 2016; 5:e003078. [PMID: 26896476 PMCID: PMC4802457 DOI: 10.1161/jaha.115.003078] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Accepted: 01/02/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Diabetes is associated with prolongation of the QT interval of the electrocardiogram and enhanced dispersion of ventricular repolarization, factors that, together with atherosclerosis and myocardial ischemia, may promote the occurrence of electrical disorders. Thus, we tested the possibility that alterations in transmembrane ionic currents reduce the repolarization reserve of myocytes, leading to action potential (AP) prolongation and enhanced beat-to-beat variability of repolarization. METHODS AND RESULTS Diabetes was induced in mice with streptozotocin (STZ), and effects of hyperglycemia on electrical properties of whole heart and myocytes were studied with respect to an untreated control group (Ctrl) using electrocardiographic recordings in vivo, ex vivo perfused hearts, and single-cell patch-clamp analysis. Additionally, a newly developed algorithm was introduced to obtain detailed information of the impact of high glucose on AP profile. Compared to Ctrl, hyperglycemia in STZ-treated animals was coupled with prolongation of the QT interval, enhanced temporal dispersion of electrical recovery, and susceptibility to ventricular arrhythmias, defects observed, in part, in the Akita mutant mouse model of type I diabetes. AP was prolonged and beat-to-beat variability of repolarization was enhanced in diabetic myocytes, with respect to Ctrl cells. Density of Kv K(+) and L-type Ca(2+) currents were decreased in STZ myocytes, in comparison to cells from normoglycemic mice. Pharmacological reduction of Kv currents in Ctrl cells lengthened AP duration and increased temporal dispersion of repolarization, reiterating features identified in diabetic myocytes. CONCLUSIONS Reductions in the repolarizing K(+) currents may contribute to electrical disturbances of the diabetic heart.
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Affiliation(s)
- Marianna Meo
- Division of Cardiovascular Medicine, Departments of Anesthesia and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Olivier Meste
- Laboratoire d'Informatique, Signaux et Systèmes de Sophia Antipolis (I3S), Université Nice Sophia Antipolis, CNRS, Nice, France
| | - Sergio Signore
- Division of Cardiovascular Medicine, Departments of Anesthesia and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Andrea Sorrentino
- Division of Cardiovascular Medicine, Departments of Anesthesia and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Antonio Cannata
- Division of Cardiovascular Medicine, Departments of Anesthesia and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Yu Zhou
- Division of Cardiovascular Medicine, Departments of Anesthesia and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Alex Matsuda
- Division of Cardiovascular Medicine, Departments of Anesthesia and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA Fondazione Cardiocentro Ticino, University of Zurich, Lugano, Switzerland
| | - Marco Luciani
- Division of Cardiovascular Medicine, Departments of Anesthesia and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Ramaswamy Kannappan
- Division of Cardiovascular Medicine, Departments of Anesthesia and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Polina Goichberg
- Division of Cardiovascular Medicine, Departments of Anesthesia and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Annarosa Leri
- Division of Cardiovascular Medicine, Departments of Anesthesia and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA Fondazione Cardiocentro Ticino, University of Zurich, Lugano, Switzerland
| | - Piero Anversa
- Division of Cardiovascular Medicine, Departments of Anesthesia and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA Fondazione Cardiocentro Ticino, University of Zurich, Lugano, Switzerland
| | - Marcello Rota
- Division of Cardiovascular Medicine, Departments of Anesthesia and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA Department of Physiology, New York Medical College, Valhalla, NY
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Yuill KH, Al Kury LT, Howarth FC. Characterization of L-type calcium channel activity in atrioventricular nodal myocytes from rats with streptozotocin-induced Diabetes mellitus. Physiol Rep 2015; 3:3/11/e12632. [PMID: 26603460 PMCID: PMC4673653 DOI: 10.14814/phy2.12632] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Accepted: 10/26/2015] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular complications are common in patients with Diabetes mellitus (DM). In addition to changes in cardiac muscle inotropy, electrical abnormalities are also commonly observed in these patients. We have previously shown that spontaneous cellular electrical activity is altered in atrioventricular nodal (AVN) myocytes, isolated from the streptozotocin (STZ) rat model of type-1 DM. In this study, utilizing the same model, we have characterized the changes in L-type calcium channel activity in single AVN myocytes. Ionic currents were recorded from AVN myocytes isolated from the hearts of control rats and from those with STZ-induced diabetes. Patch-clamp recordings were used to assess the changes in cellular electrical activity in individual myocytes. Type-1 DM significantly altered the cellular characteristics of L-type calcium current. A reduction in peak ICaL density was observed, with no corresponding changes in the activation parameters of the current. L-type calcium channel current also exhibited faster time-dependent inactivation in AVN myocytes from diabetic rats. A negative shift in the voltage dependence of inactivation was also evident, and a slowing of restitution parameters. These findings demonstrate that experimentally induced type-1 DM significantly alters AVN L-type calcium channel cellular electrophysiology. These changes in ion channel activity may contribute to the abnormalities in cardiac electrical function that are associated with high mortality levels in patients with DM.
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Affiliation(s)
- Kathryn H Yuill
- Department of Biological, Biomedical and Analytical Sciences, University of the West of England, Bristol, United Kingdom
| | - Lina T Al Kury
- College of Sustainability Sciences and Humanities, Zayed University, Abu Dhabi, UAE
| | - Frank Christopher Howarth
- Department of Physiology, Faculty of Medicine & Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, UAE
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Murfitt L, Whiteley G, Iqbal MM, Kitmitto A. Targeting caveolin-3 for the treatment of diabetic cardiomyopathy. Pharmacol Ther 2015; 151:50-71. [PMID: 25779609 DOI: 10.1016/j.pharmthera.2015.03.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 03/09/2015] [Indexed: 12/21/2022]
Abstract
Diabetes is a global health problem with more than 550 million people predicted to be diabetic by 2030. A major complication of diabetes is cardiovascular disease, which accounts for over two-thirds of mortality and morbidity in diabetic patients. This increased risk has led to the definition of a diabetic cardiomyopathy phenotype characterised by early left ventricular dysfunction with normal ejection fraction. Here we review the aetiology of diabetic cardiomyopathy and explore the involvement of the protein caveolin-3 (Cav3). Cav3 forms part of a complex mechanism regulating insulin signalling and glucose uptake, processes that are impaired in diabetes. Further, Cav3 is key for stabilisation and trafficking of cardiac ion channels to the plasma membrane and so contributes to the cardiac action potential shape and duration. In addition, Cav3 has direct and indirect interactions with proteins involved in excitation-contraction coupling and so has the potential to influence cardiac contractility. Significantly, both impaired contractility and rhythm disturbances are hallmarks of diabetic cardiomyopathy. We review here how changes to Cav3 expression levels and altered relationships with interacting partners may be contributory factors to several of the pathological features identified in diabetic cardiomyopathy. Finally, the review concludes by considering ways in which levels of Cav3 may be manipulated in order to develop novel therapeutic approaches for treating diabetic cardiomyopathy.
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Affiliation(s)
- Lucy Murfitt
- Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, M13 9NT, UK
| | - Gareth Whiteley
- Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, M13 9NT, UK
| | - Mohammad M Iqbal
- Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, M13 9NT, UK
| | - Ashraf Kitmitto
- Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, M13 9NT, UK.
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Lu C, Sun Z, Wang L. Inhibition of L-type Ca(2+) current by ginsenoside Rd in rat ventricular myocytes. J Ginseng Res 2015; 39:169-77. [PMID: 26045691 PMCID: PMC4452530 DOI: 10.1016/j.jgr.2014.11.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 10/01/2014] [Accepted: 11/02/2014] [Indexed: 11/28/2022] Open
Abstract
Background Ginsenoside Rd (GSRd), one of the most abundant ingredients of Panax ginseng, protects the heart via multiple mechanisms including the inhibition of Ca2+ influx. We intended to explore the effects of GSRd on L-type Ca2+ current (ICa,L) and define the mechanism of the suppression of ICa,L by GSRd. Methods Perforated-patch recording and whole-cell voltage clamp techniques were applied in isolated rat ventricular myocytes. Results (1) GSRd reduced ICa,L peak amplitude in a concentration-dependent manner [half-maximal inhibitory concentration (IC50) = 32.4 ± 7.1 μmol/L] and up-shifted the current–voltage (I–V) curve. (2) GSRd (30 μmol/L) significantly changed the steady-state activation curve of ICa,L (V0.5: −19.12 ± 0.68 vs. −16.26 ± 0.38 mV; n = 5, p < 0.05) and slowed down the recovery of ICa,L from inactivation [the time content (ζ) from 91 ms to 136 ms, n = 5, p < 0.01]. (3) A more significant inhibitive effect of GSRd (100 μmol/L) was identified in perforated-patch recording when compared with whole-cell recording [65.7 ± 3.2% (n = 10) vs. 31.4 ± 5.2% (n = 5), p < 0.01]. (4) Pertussis toxin (Giprotein inhibitor) completely abolished the ICa,L inhibition induced by GSRd. There was a significant difference in inhibition potency between the two cyclic adenosine monophosphate elevating agents (isoprenaline and forskolin) prestimulation [55 ± 7.8% (n = 5) vs. 17.2 ± 3.5% (n = 5), p < 0.01]. (5) 1H-[1,2,4]Oxadiazolo[4,3-a]-quinoxalin-1-one (a guanylate cyclase inhibitor) and N-acetyl-l-cysteine (a nitric oxide scavenger) partly recovered the ICa,L inhibition induced by GSRd. (6) Phorbol-12-myristate-13-acetate (a protein kinase C activator) and GF109203X (a protein kinase C inhibitor) did not contribute to the inhibition of GSRd. Conclusion These findings suggest that GSRd could inhibit ICa,L through pertussis toxin-sensitive G protein (Gi) and a nitric oxide–cyclic guanosine monophosphate-dependent mechanism.
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Affiliation(s)
- Cheng Lu
- Department of Otorhinolaryngology, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China
| | - Zhijun Sun
- Department of Cardiology, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China
| | - Line Wang
- Department of Otorhinolaryngology, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China
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Krishnaswamy PS, Egom EE, Moghtadaei M, Jansen HJ, Azer J, Bogachev O, Mackasey M, Robbins C, Rose RA. Altered parasympathetic nervous system regulation of the sinoatrial node in Akita diabetic mice. J Mol Cell Cardiol 2015; 82:125-35. [DOI: 10.1016/j.yjmcc.2015.02.024] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 02/21/2015] [Accepted: 02/26/2015] [Indexed: 11/26/2022]
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Ballou LM, Lin RZ, Cohen IS. Control of cardiac repolarization by phosphoinositide 3-kinase signaling to ion channels. Circ Res 2015; 116:127-37. [PMID: 25552692 DOI: 10.1161/circresaha.116.303975] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Upregulation of phosphoinositide 3-kinase (PI3K) signaling is a common alteration in human cancer, and numerous drugs that target this pathway have been developed for cancer treatment. However, recent studies have implicated inhibition of the PI3K signaling pathway as the cause of a drug-induced long-QT syndrome in which alterations in several ion currents contribute to arrhythmogenic drug activity. Surprisingly, some drugs that were thought to induce long-QT syndrome by direct block of the rapid delayed rectifier (IKr) also seem to inhibit PI3K signaling, an effect that may contribute to their arrhythmogenicity. The importance of PI3K in regulating cardiac repolarization is underscored by evidence that QT interval prolongation in diabetes mellitus also may result from changes in multiple currents because of decreased insulin activation of PI3K in the heart. How PI3K signaling regulates ion channels to control the cardiac action potential is poorly understood. Hence, this review summarizes what is known about the effect of PI3K and its downstream effectors, including Akt, on sodium, potassium, and calcium currents in cardiac myocytes. We also refer to some studies in noncardiac cells that provide insight into potential mechanisms of ion channel regulation by this signaling pathway in the heart. Drug development and safety could be improved with a better understanding of the mechanisms by which PI3K regulates cardiac ion channels and the extent to which PI3K inhibition contributes to arrhythmogenic susceptibility.
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Affiliation(s)
- Lisa M Ballou
- From the Department of Physiology and Biophysics and the Institute for Molecular Cardiology, Stony Brook University, NY (L.M.B., R.Z.L., I.S.C.); and the Medical Service, Northport VA Medical Center, NY (R.Z.L.)
| | - Richard Z Lin
- From the Department of Physiology and Biophysics and the Institute for Molecular Cardiology, Stony Brook University, NY (L.M.B., R.Z.L., I.S.C.); and the Medical Service, Northport VA Medical Center, NY (R.Z.L.).
| | - Ira S Cohen
- From the Department of Physiology and Biophysics and the Institute for Molecular Cardiology, Stony Brook University, NY (L.M.B., R.Z.L., I.S.C.); and the Medical Service, Northport VA Medical Center, NY (R.Z.L.).
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Fuentes-Antrás J, Picatoste B, Gómez-Hernández A, Egido J, Tuñón J, Lorenzo Ó. Updating experimental models of diabetic cardiomyopathy. J Diabetes Res 2015; 2015:656795. [PMID: 25973429 PMCID: PMC4417999 DOI: 10.1155/2015/656795] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Revised: 03/26/2015] [Accepted: 03/29/2015] [Indexed: 11/17/2022] Open
Abstract
Diabetic cardiomyopathy entails a serious cardiac dysfunction induced by alterations in structure and contractility of the myocardium. This pathology is initiated by changes in energy substrates and occurs in the absence of atherothrombosis, hypertension, or other cardiomyopathies. Inflammation, hypertrophy, fibrosis, steatosis, and apoptosis in the myocardium have been studied in numerous diabetic experimental models in animals, mostly rodents. Type I and type II diabetes were induced by genetic manipulation, pancreatic toxins, and fat and sweet diets, and animals recapitulate the main features of human diabetes and related cardiomyopathy. In this review we update and discuss the main experimental models of diabetic cardiomyopathy, analysing the associated metabolic, structural, and functional abnormalities, and including current tools for detection of these responses. Also, novel experimental models based on genetic modifications of specific related genes have been discussed. The study of specific pathways or factors responsible for cardiac failures may be useful to design new pharmacological strategies for diabetic patients.
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Affiliation(s)
- J. Fuentes-Antrás
- IIS-Fundación Jiménez Díaz, Autónoma University, 28040 Madrid, Spain
| | - B. Picatoste
- IIS-Fundación Jiménez Díaz, Autónoma University, 28040 Madrid, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) Network, 28040 Madrid, Spain
| | - A. Gómez-Hernández
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) Network, 28040 Madrid, Spain
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain
| | - J. Egido
- IIS-Fundación Jiménez Díaz, Autónoma University, 28040 Madrid, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) Network, 28040 Madrid, Spain
| | - J. Tuñón
- IIS-Fundación Jiménez Díaz, Autónoma University, 28040 Madrid, Spain
| | - Ó. Lorenzo
- IIS-Fundación Jiménez Díaz, Autónoma University, 28040 Madrid, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) Network, 28040 Madrid, Spain
- *Ó. Lorenzo:
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Pereira L, Ruiz-Hurtado G, Rueda A, Mercadier JJ, Benitah JP, Gómez AM. Calcium signaling in diabetic cardiomyocytes. Cell Calcium 2014; 56:372-80. [PMID: 25205537 DOI: 10.1016/j.ceca.2014.08.004] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Revised: 07/24/2014] [Accepted: 08/07/2014] [Indexed: 12/18/2022]
Abstract
Diabetes mellitus is one of the most common medical conditions. It is associated to medical complications in numerous organs and tissues, of which the heart is one of the most important and most prevalent organs affected by this disease. In fact, cardiovascular complications are the most common cause of death among diabetic patients. At the end of the 19th century, the weakness of the heart in diabetes was noted as part of the general muscular weakness that exists in that disease. However, it was only in the eighties that diabetic cardiomyopathy was recognized, which comprises structural and functional abnormalities in the myocardium in diabetic patients even in the absence of coronary artery disease or hypertension. This disorder has been associated with both type 1 and type 2 diabetes, and is characterized by early-onset diastolic dysfunction and late-onset systolic dysfunction, in which alteration in Ca(2+) signaling is of major importance, since it controls not only contraction, but also excitability (and therefore is involved in rhythmic disorder), enzymatic activity, and gene transcription. Here we attempt to give a brief overview of Ca(2+) fluxes alteration reported on diabetes, and provide some new data on differential modulation of Ca(2+) handling alteration in males and females type 2 diabetic mice to promote further research. Due to space limitations, we apologize for those authors whose important work is not cited.
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Affiliation(s)
- Laetitia Pereira
- Department of Pharmacology, University of California Davis, Davis, CA 95616, USA
| | - Gema Ruiz-Hurtado
- Unidad de Hipertensión, Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain; Instituto Pluridisciplinar, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain
| | - Angélica Rueda
- Departamento de Bioquímica, Cinvestav-IPN, México, DF, Mexico
| | - Jean-Jacques Mercadier
- Inserm, UMR S769, Faculté de Pharmacie, Université Paris Sud, Labex LERMIT, DHU TORINO, Châtenay-Malabry, France; Université Paris Diderot - Sorbonne Paris Cité, Assistance Publique - Hôpitaux de Paris (AP-HP), France
| | - Jean-Pierre Benitah
- Inserm, UMR S769, Faculté de Pharmacie, Université Paris Sud, Labex LERMIT, DHU TORINO, Châtenay-Malabry, France
| | - Ana María Gómez
- Inserm, UMR S769, Faculté de Pharmacie, Université Paris Sud, Labex LERMIT, DHU TORINO, Châtenay-Malabry, France.
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48
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Li S, Chen JDZ. Decreased L-type calcium current in antral smooth muscle cells of STZ-induced diabetic rats. Neurogastroenterol Motil 2014; 26:971-9. [PMID: 24758401 DOI: 10.1111/nmo.12351] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Accepted: 03/28/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND Diabetic gastroparesis (delayed gastric emptying) is associated with antral hypomotility. L-type Ca(2+) channels play an important role in generation of action potentials and activation of contractions. This study was designed to investigate if the function of the L-type Ca(2+) channels of antral circular smooth muscle cells (SMCs) is impaired in streptozotocin (STZ)-induced diabetic rats. METHODS Eight weeks after the injection of STZ or vehicle, whole-cell patch clamp was used to record Ca(2+) currents, and isometric tension recording was used to measure Ca(2+) influx-induced contractions in circular muscle strips. Solid gastric emptying was measured in diabetic and control rats. Protein expression of Ca(2+) αlC-subunit in antral smooth muscles was compared between diabetic and control rats. KEY RESULTS (1) Solid gastric emptying, independent of age or bodyweight, was slower in the diabetic rats, even after acute correction of hyperglycemia. (2) Verapamil, a potent calcium channel blocker, dose dependently reduced solid gastric emptying in normal rats. (3) Current density of L-type Ca(2+) channel at 10 mV in antral circular SMCs was significantly decreased in the diabetic rats (-9.8 ± 0.7 pA/pF vs -15.9 ± 1.0 pA/pF in control, p < 0.001). However, protein expression of the Ca(2+) channel in antral muscles did not differ between diabetic and control rats. (4) Contractile responses to 1 and 3 mM [Ca(2+) ] were significantly reduced in the diabetic antral circular muscle strips, indicative of reduced Ca(2+) influx. CONCLUSIONS & INFERENCES These data suggested that the decreased L-type Ca(2+) current in antral SMCs may contribute to antral hypomotility in STZ-induced diabetic rats.
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Affiliation(s)
- S Li
- Veterans Research and Education Foundation, VA Medical Center, Oklahoma City, OK, USA
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49
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Wu CYC, Chen B, Jiang YP, Jia Z, Martin DW, Liu S, Entcheva E, Song LS, Lin RZ. Calpain-dependent cleavage of junctophilin-2 and T-tubule remodeling in a mouse model of reversible heart failure. J Am Heart Assoc 2014; 3:e000527. [PMID: 24958777 PMCID: PMC4309042 DOI: 10.1161/jaha.113.000527] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background A highly organized transverse tubule (T‐tubule) network is necessary for efficient Ca2+‐induced Ca2+ release and synchronized contraction of ventricular myocytes. Increasing evidence suggests that T‐tubule remodeling due to junctophilin‐2 (JP‐2) downregulation plays a critical role in the progression of heart failure. However, the mechanisms underlying JP‐2 dysregulation remain incompletely understood. Methods and Results A mouse model of reversible heart failure that is driven by conditional activation of the heterotrimeric G protein Gαq in cardiac myocytes was used in this study. Mice with activated Gαq exhibited disruption of the T‐tubule network and defects in Ca2+ handling that culminated in heart failure compared with wild‐type mice. Activation of Gαq/phospholipase Cβ signaling increased the activity of the Ca2+‐dependent protease calpain, leading to the proteolytic cleavage of JP‐2. A novel calpain cleavage fragment of JP‐2 is detected only in hearts with constitutive Gαq signaling to phospholipase Cβ. Termination of the Gαq signal was followed by normalization of the JP‐2 protein level, repair of the T‐tubule network, improvements in Ca2+ handling, and reversal of heart failure. Treatment of mice with a calpain inhibitor prevented Gαq‐dependent JP‐2 cleavage, T‐tubule disruption, and the development of heart failure. Conclusions Disruption of the T‐tubule network in heart failure is a reversible process. Gαq‐dependent activation of calpain and subsequent proteolysis of JP‐2 appear to be the molecular mechanism that leads to T‐tubule remodeling, Ca2+ handling dysfunction, and progression to heart failure in this mouse model.
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Affiliation(s)
- Chia-Yen C Wu
- Department of Physiology and Biophysics and Institute of Molecular Cardiology, Stony Brook University, Stony Brook, NY (C.Y.C.W., Y.P.J., S.L., E.E., R.Z.L.)
| | - Biyi Chen
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (B.C., L.S.S.)
| | - Ya-Ping Jiang
- Department of Physiology and Biophysics and Institute of Molecular Cardiology, Stony Brook University, Stony Brook, NY (C.Y.C.W., Y.P.J., S.L., E.E., R.Z.L.)
| | - Zhiheng Jia
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY (Z.J., E.E.)
| | - Dwight W Martin
- Department of Medicine and Proteomics Center, Stony Brook University, Stony Brook, NY (D.W.M.)
| | - Shengnan Liu
- Department of Physiology and Biophysics and Institute of Molecular Cardiology, Stony Brook University, Stony Brook, NY (C.Y.C.W., Y.P.J., S.L., E.E., R.Z.L.)
| | - Emilia Entcheva
- Department of Physiology and Biophysics and Institute of Molecular Cardiology, Stony Brook University, Stony Brook, NY (C.Y.C.W., Y.P.J., S.L., E.E., R.Z.L.) Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY (Z.J., E.E.)
| | - Long-Sheng Song
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (B.C., L.S.S.)
| | - Richard Z Lin
- Department of Physiology and Biophysics and Institute of Molecular Cardiology, Stony Brook University, Stony Brook, NY (C.Y.C.W., Y.P.J., S.L., E.E., R.Z.L.) Department of Veterans Affairs Medical Center, Northport, NY (R.Z.L.)
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50
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Zhang Y, Welzig CM, Picard KL, Du C, Wang B, Pan JQ, Kyriakis JM, Aronovitz MJ, Claycomb WC, Blanton RM, Park HJ, Galper JB. Glycogen synthase kinase-3β inhibition ameliorates cardiac parasympathetic dysfunction in type 1 diabetic Akita mice. Diabetes 2014; 63:2097-113. [PMID: 24458356 PMCID: PMC4030105 DOI: 10.2337/db12-1459] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Decreased heart rate variability (HRV) is a major risk factor for sudden death and cardiovascular disease. We previously demonstrated that parasympathetic dysfunction in the heart of the Akita type 1 diabetic mouse was due to a decrease in the level of the sterol response element-binding protein (SREBP-1). Here we demonstrate that hyperactivity of glycogen synthase kinase-3β (GSK3β) in the atrium of the Akita mouse results in decreased SREBP-1, attenuation of parasympathetic modulation of heart rate, measured as a decrease in the high-frequency (HF) fraction of HRV in the presence of propranolol, and a decrease in expression of the G-protein coupled inward rectifying K(+) (GIRK4) subunit of the acetylcholine (ACh)-activated inward-rectifying K(+) channel (IKACh), the ion channel that mediates the heart rate response to parasympathetic stimulation. Treatment of atrial myocytes with the GSK3β inhibitor Kenpaullone increased levels of SREBP-1 and expression of GIRK4 and IKACh, whereas a dominant-active GSK3β mutant decreased SREBP-1 and GIRK4 expression. In Akita mice treated with GSK3β inhibitors Li(+) and/or CHIR-99021, Li(+) increased IKACh, and Li(+) and CHIR-99021 both partially reversed the decrease in HF fraction while increasing GIRK4 and SREBP-1 expression. These data support the conclusion that increased GSK3β activity in the type 1 diabetic heart plays a critical role in parasympathetic dysfunction through an effect on SREBP-1, supporting GSK3β as a new therapeutic target for diabetic autonomic neuropathy.
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Affiliation(s)
- Yali Zhang
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA
| | - Charles M Welzig
- Departments of Neurology and Physiology, Medical College of Wisconsin, Milwaukee, WIDepartment of Medicine, Tufts University School of Medicine, Boston, MA
| | - Kristen L Picard
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA
| | - Chuang Du
- Department of Neuroscience, Tufts University School of Medicine, Boston, MA
| | - Bo Wang
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA
| | - Jen Q Pan
- Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA
| | - John M Kyriakis
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA
| | - Mark J Aronovitz
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA
| | - William C Claycomb
- Department of Biochemistry & Molecular Biology, Louisiana State University School of Medicine, New Orleans, LA
| | - Robert M Blanton
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MADepartment of Medicine, Tufts University School of Medicine, Boston, MA
| | - Ho-Jin Park
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA
| | - Jonas B Galper
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MADepartment of Medicine, Tufts University School of Medicine, Boston, MA
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