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Zhang Y, Du M, Zhu B, Ma R, Zhang J. Human umbilical cord mesenchymal stem cell-derived exosomal miR-455-3p targets CAMK2N1 to improve trophoblast cell injury in gestational diabetes mellitus. Diabetol Metab Syndr 2025; 17:138. [PMID: 40287773 PMCID: PMC12032689 DOI: 10.1186/s13098-025-01692-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 04/03/2025] [Indexed: 04/29/2025] Open
Abstract
OBJECTIVE We aimed to probe the effect of microRNA (miR)-455-3p derived from human umbilical cord mesenchymal stem cell exosomes (hucMSCs-Exos) in targeting calcium/calmodulin-dependent protein kinase 2 inhibitor 1 (CAMK2N1) to mitigate trophoblast cell injury in gestational diabetes mellitus (GDM). METHODS hucMSCs were cultured, and Exos were isolated and characterized using transmission electron microscopy and Western blot (WB) for exosomal surface markers CD63, TSG101, and Calnexin. An in vitro GDM model was established by exposing human trophoblast cells (HRT-8/SVneo) to high glucose (HG), followed by intervention with Exos or overexpression of CAMK2N1. RT-qPCR or WB was applied to test miR-455-3p and CAMK2N1 expression levels. CCK-8 assay was adopted to assess cell proliferation, Transwell assay was applied to test cell migration, and flow cytometry was implemented to assess cell apoptosis. Bioinformatics websites and a dual-luciferase reporter gene assay were conducted to verify the targeting relationship between miR-455-3p and CAMK2N1. RESULTS The successfully isolated Exos expressed the exosomal markers CD63 and TSG101. Treatment with hucMSCs-Exos and hucMSCs-Exos carrying miR-455-3p mimic enhanced the migration and proliferation of HG-induced HRT-8/SVneo cells while reducing cell apoptosis. In contrast, the miR-455-3p inhibitor and overexpression of CAMK2N1 reversed these protective effects, leading to decreased cell migration and proliferation and increased apoptosis. Furthermore, bioinformatics analysis and experimental validation confirmed that miR-455-3p directly targeted and negatively regulated CAMK2N1. CONCLUSION miR-455-3p derived from hucMSCs-Exos exerts a protective effect against trophoblast cell injury in GDM by targeting and downregulating CAMK2N1.
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Affiliation(s)
- Yan Zhang
- Department of Medical Genetics, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Xishan District, Kunming, Yunnan, 650000, China
- National Health Commission Key Laboratory of Preconception Health Birth in Western China, Kunming, Yunan, China
- Department of Medical Genetics, Yunnan Provincial Key Laboratory of Birth Defects and Genetic Diseases, NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China, Kunming, Yunan, China
| | - Mingyu Du
- Department of Obstetrics, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, China
| | - Baosheng Zhu
- Department of Medical Genetics, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Xishan District, Kunming, Yunnan, 650000, China
- National Health Commission Key Laboratory of Preconception Health Birth in Western China, Kunming, Yunan, China
- Department of Medical Genetics, Yunnan Provincial Key Laboratory of Birth Defects and Genetic Diseases, NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China, Kunming, Yunan, China
| | - Runmei Ma
- Department of Obstetrics, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, China
| | - Jinman Zhang
- Department of Medical Genetics, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Xishan District, Kunming, Yunnan, 650000, China.
- National Health Commission Key Laboratory of Preconception Health Birth in Western China, Kunming, Yunan, China.
- Department of Medical Genetics, Yunnan Provincial Key Laboratory of Birth Defects and Genetic Diseases, NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China, Kunming, Yunan, China.
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Nie P, Zhang R, Jia T, Huang J, Xu H. Knockout of TRPM2 protects against cyclophosphamide-induced premature ovarian failure via inhibiting AMPK/p53 signaling pathway. Chem Biol Interact 2025; 409:111426. [PMID: 39952379 DOI: 10.1016/j.cbi.2025.111426] [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: 09/16/2024] [Revised: 02/05/2025] [Accepted: 02/11/2025] [Indexed: 02/17/2025]
Abstract
The global prevalence of premature ovarian failure (POF) is from 3.1 % to 4.3 %, which is a multifactorial disease including genetics, environmental and medical factors. However, the occurrence of POF is not well understood. To further explore the potential mechanism of POF, cyclophosphamide (CTX) was used to construct the model of POF. Additionally, the occurrence of POF was related to oxidative stress, apoptosis, proliferation and others. Ca2+ is essential for almost all life processes. Therefore, TRPM2-deficient mice was used to explore the role of Ca2+ in POF. The results indicated that the mouse serum E2 and AMH levels decreased, FSH and LH levels increased, and the activity of antioxidant enzymes including CAT, SOD and GSH decreased with mtROS accumulation in the ovary, thereby causing ovarian DNA damage, promoting ovarian cell apoptosis and inhibiting cell proliferation after wild-type mice exposed to CTX. Notably, these indicators have improved after TRPM2-/-. Based on these, we have further proved that the activation TRPM2 channel could lead to intracellular Ca2+ overload, plentiful Ca2+ bind to calmodulin accompanied with mitochondrial ROS accumulation, thereby activating AMPK/p53 signaling pathway, inducing proliferation arrest and excessive apoptosis. We hope to provide therapeutic targets to prevent the occurrence of POF by studying the potential mechanism of POF.
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Affiliation(s)
- Penghui Nie
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang, 330047, China
| | - Ruiying Zhang
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang, 330047, China; The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, 330000, China
| | - Tiantian Jia
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang, 330047, China
| | - Jialyu Huang
- Center for Reproductive Medicine, Jiangxi Key Laboratory of Reproductive Health, Jiangxi Maternal and Child Health Hospital, Nanchang Medical College, Nanchang, China.
| | - Hengyi Xu
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang, 330047, China.
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Wu J, Chen Q, Zou JZ, Chen YY, Chen HH, Lin YY, Huang XD. Association between hepatic steatosis index and glucose status conversion from impaired fasting glucose base on Chinese adults: a cohort study from real-world. Eur J Med Res 2025; 30:100. [PMID: 39953638 PMCID: PMC11827240 DOI: 10.1186/s40001-025-02354-4] [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: 10/28/2024] [Accepted: 02/03/2025] [Indexed: 02/17/2025] Open
Abstract
OBJECTIVE Evidence regarding the relationship between the hepatic steatosis index (HSI) and glycemic conversion outcomes in individuals with impaired fasting glucose (IFG) is still limited. Our study aims to explore the role of HSI in the reversion to normoglycemia or the progression to diabetes among Chinese IFG individuals. METHODS We conducted a retrospective analysis using data from 11,327 IFG individuals who had undergone wellness examinations at Rich Healthcare Group. To analyze the association between the baseline HSI and glucose status conversion, a Cox regression model was used, and the hazard ratio (HR) and 95% confidence interval (CI) were computed. A generalized additive model was used to examine non-linear relationships. A two-piecewise binary logistic regression model was employed to further elucidate the non-linearity. Sensitivity and subgroup analyses were also conducted. RESULTS Over an observation period spanning 33,892 person-years, the rate of normoglycemia reversion was found to be 41.75%, whereas the rate of progression to diabetes was 11.63%. After accounting for potential confounding variables, our analysis demonstrated that among IFG individuals, there was an inverse relationship between HSI and the likelihood of returning to normoglycemia (HR = 0.93, 95% CI: 0.90-0.96, P < 0.001), and a positive association between the HSI and progression to diabetes (HR = 1.49, 95% CI: 1.40-1.58, P < 0.001). The smooth curve-fitting plot revealed a nonlinear association between the HSI and diabetes progression, with inflection points at 26.55 and 40.74. Sensitivity analysis and subgroup analysis confirmed the stability of the study's findings. CONCLUSION HSI was significantly linked to normoglycemia reversion and diabetes progression in IFG individuals, indicating its potential as a risk indicator for diabetes and a guide for prevention strategies. However, further research is needed to confirm this.
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Affiliation(s)
- Juan Wu
- Department of Laboratory Medicine, Jieyang People's Hospital, No. 107 Tianfu Road, Rongcheng District, Jieyang, Guangdong, China
| | - Qi Chen
- Department of Laboratory Medicine, Jieyang People's Hospital, No. 107 Tianfu Road, Rongcheng District, Jieyang, Guangdong, China
| | - Jun-Zhong Zou
- Department of Laboratory Medicine, Jieyang People's Hospital, No. 107 Tianfu Road, Rongcheng District, Jieyang, Guangdong, China
| | - Yi-Ying Chen
- Department of Laboratory Medicine, Jieyang People's Hospital, No. 107 Tianfu Road, Rongcheng District, Jieyang, Guangdong, China
| | - Hua-Hong Chen
- Department of Laboratory Medicine, Jieyang People's Hospital, No. 107 Tianfu Road, Rongcheng District, Jieyang, Guangdong, China
| | - Yu-Ye Lin
- Department of Laboratory Medicine, Jieyang People's Hospital, No. 107 Tianfu Road, Rongcheng District, Jieyang, Guangdong, China
| | - Xu-Dong Huang
- Department of Laboratory Medicine, Jieyang People's Hospital, No. 107 Tianfu Road, Rongcheng District, Jieyang, Guangdong, China.
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Mattiazzi A, Jaquenod De Giusti C, Valverde CA. CaMKII at the crossroads: calcium dysregulation, and post-translational modifications driving cell death. J Physiol 2025. [PMID: 39907446 DOI: 10.1113/jp285941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 01/08/2025] [Indexed: 02/06/2025] Open
Abstract
The multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates numerous proteins involved in excitation-contraction-relaxation coupling and cardiac excitability. However, its overactivation induces severe Ca2+/handling alterations, playing a significant role in the pathogenesis of diseases such as hypertrophy, arrhythmias and cell death, which can ultimately lead to heart failure. Being a suitable target for various aberrant signals that characterize several diseases, such as Ca2+ overload, oxidative stress or excessive glycosylation, CaMKII shifts under these conditions from a physiological regulator to a pathological molecule. In this review, we explore the evolution of knowledge regarding the role of CaMKII activation on cell death across different pathological contexts, focusing on the converging mechanisms that transform the enzyme from an ally into a villain.
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Affiliation(s)
- Alicia Mattiazzi
- Centro de Investigaciones Cardiovasculares 'Dr Horacio E. Cingolani,' CCT-La Plata/CONICET, Facultad de Ciencias Médicas, UNLP, La Plata, Argentina
| | - Carolina Jaquenod De Giusti
- Centro de Investigaciones Cardiovasculares 'Dr Horacio E. Cingolani,' CCT-La Plata/CONICET, Facultad de Ciencias Médicas, UNLP, La Plata, Argentina
| | - Carlos A Valverde
- Centro de Investigaciones Cardiovasculares 'Dr Horacio E. Cingolani,' CCT-La Plata/CONICET, Facultad de Ciencias Médicas, UNLP, La Plata, Argentina
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Pereyra EV, Godoy Coto J, Velez Rueda JO, Cavalli FA, González Arbelaez LF, Fantinelli JC, Aranda O, Colman Lerner JE, Portiansky EL, Mosca SM, Ennis IL. Beneficial Consequences of One-Month Oral Treatment with Cannabis Oil on Cardiac Hypertrophy and the Mitochondrial Pool in Spontaneously Hypertensive Rats. Cannabis Cannabinoid Res 2025; 10:e134-e144. [PMID: 39137344 DOI: 10.1089/can.2024.0066] [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] [Indexed: 08/15/2024] Open
Abstract
Introduction: It has been demonstrated the dysregulation of the cardiac endocannabinoid system in cardiovascular diseases. Thus, the modulation of this system through the administration of phytocannabinoids present in medicinal cannabis oil (CO) emerges as a promising therapeutic approach. Furthermore, phytocannabinoids exhibit potent antioxidant properties, making them highly desirable in the treatment of cardiac pathologies, such as hypertension-induced cardiac hypertrophy (CH). Objective: To evaluate the effect of CO treatment on hypertrophy and mitochondrial status in spontaneously hypertensive rat (SHR) hearts. Methods: Three-month-old male SHR were randomly assigned to CO or olive oil (vehicle) oral treatment for 1 month. We evaluated cardiac mass and histology, mitochondrial dynamics, membrane potential, area and density, myocardial reactive oxygen species (ROS) production, superoxide dismutase (SOD), and citrate synthase (CS) activity and expression. Data are presented as mean ± SEM (n) and compared by t-test, or two-way ANOVA and Bonferroni post hoc test were used as appropriate. p < 0.05 was considered statistically significant. Results: CH was reduced by CO treatment, as indicated by the left ventricular weight/tibia length ratio, left ventricular mass index, myocyte cross-sectional area, and left ventricle collagen volume fraction. The ejection fraction was preserved in the CO-treated group despite the persistence of elevated systolic blood pressure and the reduction in CH. Mitochondrial membrane potential was improved and mitochondrial biogenesis, dynamics, area, and density were all increased by treatment. Moreover, the activity and expression of the CS were enhanced by treatment, whereas ROS production was decreased and the antioxidant activity of SOD increased by CO administration. Conclusion: Based on the mentioned results, we propose that 1-month oral treatment with CO is effective to reduce hypertrophy, improve the mitochondrial pool and increase the antioxidant capacity in SHR hearts.
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Affiliation(s)
- Erica Vanesa Pereyra
- Centro de Investigaciones Cardiovasculares "Horacio E. Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP) - CONICET, La Plata, Argentina
| | - Joshua Godoy Coto
- Centro de Investigaciones Cardiovasculares "Horacio E. Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP) - CONICET, La Plata, Argentina
| | - Jorge Omar Velez Rueda
- Centro de Investigaciones Cardiovasculares "Horacio E. Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP) - CONICET, La Plata, Argentina
| | - Fiorella Anabel Cavalli
- Centro de Investigaciones Cardiovasculares "Horacio E. Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP) - CONICET, La Plata, Argentina
| | - Luisa Fernanda González Arbelaez
- Centro de Investigaciones Cardiovasculares "Horacio E. Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP) - CONICET, La Plata, Argentina
| | - Juliana Catalina Fantinelli
- Centro de Investigaciones Cardiovasculares "Horacio E. Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP) - CONICET, La Plata, Argentina
| | - Oswaldo Aranda
- Programa Ambiental de extensión universitaria (PAEU). Facultad de Ciencias Exactas UNLP, La Plata, Argentina
| | | | - Enrique Leo Portiansky
- Laboratorio de Análisis de Imágenes, Facultad de Ciencias Veterinarias, UNLP, La Plata, Argentina
| | - Susana Maria Mosca
- Centro de Investigaciones Cardiovasculares "Horacio E. Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP) - CONICET, La Plata, Argentina
| | - Irene Lucia Ennis
- Centro de Investigaciones Cardiovasculares "Horacio E. Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP) - CONICET, La Plata, Argentina
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Deb A, Tow BD, Hao J, Nguyen BL, Gomez V, Stewart JA, Smuder AJ, Knollmann BC, Wang Y, Liu B. Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY PLUS 2024; 10:100093. [PMID: 39691471 PMCID: PMC11651627 DOI: 10.1016/j.jmccpl.2024.100093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2024]
Abstract
Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmic syndrome caused by mutations in the calcium (Ca2+) release channel ryanodine receptor (RyR2) and its accessory proteins. These mutations make the channel leaky, resulting in Ca2+-dependent arrhythmias. Besides arrhythmias, CPVT hearts typically lack structural cardiac remodeling, a characteristic often observed in other cardiac conditions (heart failure, prediabetes) also marked by RyR2 leak. Recent studies suggest that mitochondria are able to accommodate more Ca2+ influx to inhibit arrhythmias in CPVT. Thus, we hypothesize that CPVT mitochondria can absorb diastolic Ca2+ to protect the heart from cardiac remodeling. Methods and results The Mitochondrial Ca2+ uniporter (MCU), the main mitochondrial Ca2+ uptake protein, was conditionally knocked out in a CPVT model of calsequestrin 2 (CASQ2) KO. In vivo cardiac function was impaired in the CASQ2-/--MCUCKO model as assessed by echocardiography. Cardiac dilation and cellular hypertrophy were also observed in the CASQ2-/--MCUCKO hearts. Live-cell imaging identified altered Ca2+ handling and increased oxidative stress in CASQ2-/--MCUCKO myocytes. The activation status of Ca2+-dependent remodeling pathways (CaMKII, Calcineurin) was not altered in the CASQ2-/--MCUCKO model. RNAseq identified changes in the transcriptome of the CASQ2-/--MCUCKO hearts, distinct from the classic cardiac remodeling program of fetal gene re-expression. Conclusions We present genetic evidence that mitochondria play a protective role in CPVT. MCU-dependent Ca2+ uptake is crucial for preventing pathological cardiac remodeling in CPVT.
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Affiliation(s)
- Arpita Deb
- Department of Biological Sciences, Mississippi State University, Starkville, MS 39762, USA
| | - Brian D. Tow
- Department of Biological Sciences, Mississippi State University, Starkville, MS 39762, USA
| | - Jie Hao
- Plant Pathology Department, University of Florida, Gainesville, FL 32611, USA
| | - Branden L. Nguyen
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611, USA
| | - Valeria Gomez
- Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA
| | - James A. Stewart
- School of Pharmacy, Department of BioMolecular Sciences, University of Mississippi, Oxford, MS 38677, USA
| | - Ashley J. Smuder
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611, USA
| | - Bjorn C. Knollmann
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Ying Wang
- Department of Biological Sciences, Mississippi State University, Starkville, MS 39762, USA
- Plant Pathology Department, University of Florida, Gainesville, FL 32611, USA
| | - Bin Liu
- Department of Biological Sciences, Mississippi State University, Starkville, MS 39762, USA
- Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA
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Galis P, Bartosova L, Farkasova V, Bartekova M, Ferenczyova K, Rajtik T. Update on clinical and experimental management of diabetic cardiomyopathy: addressing current and future therapy. Front Endocrinol (Lausanne) 2024; 15:1451100. [PMID: 39140033 PMCID: PMC11319149 DOI: 10.3389/fendo.2024.1451100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 07/12/2024] [Indexed: 08/15/2024] Open
Abstract
Diabetic cardiomyopathy (DCM) is a severe secondary complication of type 2 diabetes mellitus (T2DM) that is diagnosed as a heart disease occurring in the absence of any previous cardiovascular pathology in diabetic patients. Although it is still lacking an exact definition as it combines aspects of both pathologies - T2DM and heart failure, more evidence comes forward that declares DCM as one complex disease that should be treated separately. It is the ambiguous pathological phenotype, symptoms or biomarkers that makes DCM hard to diagnose and screen for its early onset. This re-view provides an updated look on the novel advances in DCM diagnosis and treatment in the experimental and clinical settings. Management of patients with DCM proposes a challenge by itself and we aim to help navigate and advice clinicians with early screening and pharmacotherapy of DCM.
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Affiliation(s)
- Peter Galis
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Bratislava, Slovakia
| | - Linda Bartosova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Bratislava, Slovakia
| | - Veronika Farkasova
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Monika Bartekova
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
- Institute of Physiology, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia
| | - Kristina Ferenczyova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Bratislava, Slovakia
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Tomas Rajtik
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Bratislava, Slovakia
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
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Ye W, Han K, Xie M, Li S, Chen G, Wang Y, Li T. Mitochondrial energy metabolism in diabetic cardiomyopathy: Physiological adaption, pathogenesis, and therapeutic targets. Chin Med J (Engl) 2024; 137:936-948. [PMID: 38527931 PMCID: PMC11046025 DOI: 10.1097/cm9.0000000000003075] [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: 07/08/2023] [Indexed: 03/27/2024] Open
Abstract
Diabetic cardiomyopathy is defined as abnormal structure and function of the heart in the setting of diabetes, which could eventually develop heart failure and leads to the death of the patients. Although blood glucose control and medications to heart failure show beneficial effects on this disease, there is currently no specific treatment for diabetic cardiomyopathy. Over the past few decades, the pathophysiology of diabetic cardiomyopathy has been extensively studied, and an increasing number of studies pinpoint that impaired mitochondrial energy metabolism is a key mediator as well as a therapeutic target. In this review, we summarize the latest research in the field of diabetic cardiomyopathy, focusing on mitochondrial damage and adaptation, altered energy substrates, and potential therapeutic targets. A better understanding of the mitochondrial energy metabolism in diabetic cardiomyopathy may help to gain more mechanistic insights and generate more precise mitochondria-oriented therapies to treat this disease.
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Affiliation(s)
- Wanlin Ye
- Department of Anesthesiology, Laboratory of Mitochondria and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Kun Han
- Department of Anesthesiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, Sichuan 610041, China
| | - Maodi Xie
- Department of Anesthesiology, Laboratory of Mitochondria and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Sheyu Li
- Department of Endocrinology and Metabolism, Division of Guideline and Rapid Recommendation, Cochrane China Center, MAGIC China Center, Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Guo Chen
- Department of Anesthesiology, Laboratory of Mitochondria and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yanyan Wang
- Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Tao Li
- Department of Anesthesiology, Laboratory of Mitochondria and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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Ren FF, Zhao L, Jiang XY, Zhang JJ, Gou JM, Yu XY, Wu SJ, Li L. Sphingosylphosphorylcholine alleviates pressure overload-induced myocardial remodeling in mice via inhibiting CaM-JNK/p38 signaling pathway. Acta Pharmacol Sin 2024; 45:312-326. [PMID: 37833535 PMCID: PMC10789762 DOI: 10.1038/s41401-023-01168-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 09/13/2023] [Indexed: 10/15/2023]
Abstract
Apoptosis plays a critical role in the development of heart failure, and sphingosylphosphorylcholine (SPC) is a bioactive sphingolipid naturally occurring in blood plasma. Some studies have shown that SPC inhibits hypoxia-induced apoptosis in myofibroblasts, the crucial non-muscle cells in the heart. Calmodulin (CaM) is a known SPC receptor. In this study we investigated the role of CaM in cardiomyocyte apoptosis in heart failure and the associated signaling pathways. Pressure overload was induced in mice by trans-aortic constriction (TAC) surgery. TAC mice were administered SPC (10 μM·kg-1·d-1) for 4 weeks post-surgery. We showed that SPC administration significantly improved survival rate and cardiac hypertrophy, and inhibited cardiac fibrosis in TAC mice. In neonatal mouse cardiomyocytes, treatment with SPC (10 μM) significantly inhibited Ang II-induced cardiomyocyte hypertrophy, fibroblast-to-myofibroblast transition and cell apoptosis accompanied by reduced Bax and phosphorylation levels of CaM, JNK and p38, as well as upregulated Bcl-2, a cardiomyocyte-protective protein. Thapsigargin (TG) could enhance CaM functions by increasing Ca2+ levels in cytoplasm. TG (3 μM) annulled the protective effect of SPC against Ang II-induced cardiomyocyte apoptosis. Furthermore, we demonstrated that SPC-mediated inhibition of cardiomyocyte apoptosis involved the regulation of p38 and JNK phosphorylation, which was downstream of CaM. These results offer new evidence for SPC regulation of cardiomyocyte apoptosis, potentially providing a new therapeutic target for cardiac remodeling following stress overload.
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Affiliation(s)
- Fang-Fang Ren
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Lin Zhao
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xian-Yun Jiang
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Jing-Jing Zhang
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Jia-Min Gou
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xiao-Yu Yu
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Shu-Jin Wu
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Lei Li
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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Li AL, Lian L, Chen XN, Cai WH, Fan XB, Fan YJ, Li TT, Xie YY, Zhang JP. The role of mitochondria in myocardial damage caused by energy metabolism disorders: From mechanisms to therapeutics. Free Radic Biol Med 2023; 208:236-251. [PMID: 37567516 DOI: 10.1016/j.freeradbiomed.2023.08.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/24/2023] [Accepted: 08/03/2023] [Indexed: 08/13/2023]
Abstract
Myocardial damage is the most serious pathological consequence of cardiovascular diseases and an important reason for their high mortality. In recent years, because of the high prevalence of systemic energy metabolism disorders (e.g., obesity, diabetes mellitus, and metabolic syndrome), complications of myocardial damage caused by these disorders have attracted widespread attention. Energy metabolism disorders are independent of traditional injury-related risk factors, such as ischemia, hypoxia, trauma, and infection. An imbalance of myocardial metabolic flexibility and myocardial energy depletion are usually the initial changes of myocardial injury caused by energy metabolism disorders, and abnormal morphology and functional destruction of the mitochondria are their important features. Specifically, mitochondria are the centers of energy metabolism, and recent evidence has shown that decreased mitochondrial function, caused by an imbalance in mitochondrial quality control, may play a key role in myocardial injury caused by energy metabolism disorders. Under chronic energy stress, mitochondria undergo pathological fission, while mitophagy, mitochondrial fusion, and biogenesis are inhibited, and mitochondrial protein balance and transfer are disturbed, resulting in the accumulation of nonfunctional and damaged mitochondria. Consequently, damaged mitochondria lead to myocardial energy depletion and the accumulation of large amounts of reactive oxygen species, further aggravating the imbalance in mitochondrial quality control and forming a vicious cycle. In addition, impaired mitochondria coordinate calcium homeostasis imbalance, and epigenetic alterations participate in the pathogenesis of myocardial damage. These pathological changes induce rapid progression of myocardial damage, eventually leading to heart failure or sudden cardiac death. To intervene more specifically in the myocardial damage caused by metabolic disorders, we need to understand the specific role of mitochondria in this context in detail. Accordingly, promising therapeutic strategies have been proposed. We also summarize the existing therapeutic strategies to provide a reference for clinical treatment and developing new therapies.
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Affiliation(s)
- Ao-Lin Li
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300183, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China; Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Lu Lian
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300183, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China; Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Xin-Nong Chen
- Department of Traditional Chinese Medicine, Tianjin First Central Hospital, Tianjin, 300190, China
| | - Wen-Hui Cai
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300183, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China; Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Xin-Biao Fan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300183, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China; Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Ya-Jie Fan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300183, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China; Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Ting-Ting Li
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300183, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China; Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Ying-Yu Xie
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China.
| | - Jun-Ping Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300183, China.
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11
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Wang J, Zhu X, Wang S, Zhang Y, Hua W, Liu Z, Zheng Y, Lu X. Phosphoproteomic and proteomic profiling in post-infarction chronic heart failure. Front Pharmacol 2023; 14:1181622. [PMID: 37405054 PMCID: PMC10315476 DOI: 10.3389/fphar.2023.1181622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 06/05/2023] [Indexed: 07/06/2023] Open
Abstract
Background: Post-infarction chronic heart failure is the most common type of heart failure. Patients with chronic heart failure show elevated morbidity and mortality with limited evidence-based therapies. Phosphoproteomic and proteomic analysis can provide insights regarding molecular mechanisms underlying post-infarction chronic heart failure and explore new therapeutic approaches. Methods and results: Global quantitative phosphoproteomic and proteomic analysis of left ventricular tissues from post-infarction chronic heart failure rats were performed. A total of 33 differentially expressed phosphorylated proteins (DPPs) and 129 differentially expressed proteins were identified. Bioinformatic analysis indicated that DPPs were enriched mostly in nucleocytoplasmic transport and mRNA surveillance pathway. Bclaf1 Ser658 was identified after construction of Protein-Protein Interaction Network and intersection with Thanatos Apoptosis Database. Predicted Upstream Kinases of DPPs based on kinase-substrate enrichment analysis (KSEA) app showed 13 kinases enhanced in heart failure. Proteomic analysis showed marked changes in protein expression related to cardiac contractility and metabolism. Conclusion: The present study marked phosphoproteomics and proteomics changes in post-infarction chronic heart failure. Bclaf1 Ser658 might play a critical role in apoptosis in heart failure. PRKAA1, PRKACA, and PAK1 might serve as potential therapeutic targets for post-infarction chronic heart failure.
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Affiliation(s)
| | | | | | | | | | | | - Yu Zheng
- *Correspondence: Yu Zheng, ; Xiao Lu,
| | - Xiao Lu
- *Correspondence: Yu Zheng, ; Xiao Lu,
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12
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Liu H, Zhou Z, Deng H, Tian Z, Wu Z, Liu X, Ren Z, Jiang Z. Trim65 attenuates isoproterenol-induced cardiac hypertrophy by promoting autophagy and ameliorating mitochondrial dysfunction via the Jak1/Stat1 signaling pathway. Eur J Pharmacol 2023; 949:175735. [PMID: 37080331 DOI: 10.1016/j.ejphar.2023.175735] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 04/10/2023] [Accepted: 04/17/2023] [Indexed: 04/22/2023]
Abstract
Pathological cardiac hypertrophy is a major cause of heart failure, and there is no effective approach for its prevention or treatment. The Trim family is a recently identified family of E3 ubiquitin ligases that regulate cardiac hypertrophy. Trim65, which is a memberof the Trim family, previous studies have not determined whether Trim65 affects cardiac hypertrophy. In this study, the effects of Trim65 on isoproterenol (ISO)-induced cardiac hypertrophy and the underlying mechanisms were investigated. In contrast to C57BL/6 mice, Trim65-knockout (Trim65-KO) mice developed more severe myocardial hypertrophy, fibrosis and cardiac dysfunction after being intraperitoneally injected with ISO for 2 weeks. Transmission electron microscopy (TEM) revealed that the autophagic flux was inhibited, mitochondria were swollen, and mitochondrial cristae were lost or decreased in the myocardium of Trim65-KO mice. In vitro studies demonstrated that overexpression of Trim65 inhibited ISO-induced cardiomyocyte hypertrophy by increasing mitochondrial density and membrane potential, and the Stat1 inhibitor fludarabine attenuated the effect of Trim65 knockdown on ISO-induced cardiomyocyte hypertrophy by reducing Reactive oxygen species (ROS) production and increasing the mitochondrial density and membrane potential. Our findings provide the first link between Trim65 and mitochondria, and we found for the first time that Trim65 inhibits mitochondria-dependent apoptosis and autophagy via the Jak1/Stat1 signalling pathway, ultimately attenuating ISO-induced cardiac hypertrophy; this effect of Trim65 might be mediated via the regulation of Jak1 ubiquitination. Taking these findings together, we suggest that genes that are related to mitochondria-dependent apoptosis and that are associated with Trim65 could be promising therapeutic targets for cardiac hypertrophy.
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Affiliation(s)
- HuiTing Liu
- Hengyang Medical College, University of South China, Hengyang City, Hunan Province, 421001, PR China
| | - ZhiXiang Zhou
- Hengyang Medical College, University of South China, Hengyang City, Hunan Province, 421001, PR China
| | - HuaNian Deng
- Hengyang Medical College, University of South China, Hengyang City, Hunan Province, 421001, PR China
| | - Zhen Tian
- Hengyang Medical College, University of South China, Hengyang City, Hunan Province, 421001, PR China
| | - ZeFan Wu
- Hengyang Medical College, University of South China, Hengyang City, Hunan Province, 421001, PR China
| | - XiYan Liu
- Hengyang Medical College, University of South China, Hengyang City, Hunan Province, 421001, PR China
| | - Zhong Ren
- Hengyang Medical College, University of South China, Hengyang City, Hunan Province, 421001, PR China
| | - ZhiSheng Jiang
- Hengyang Medical College, University of South China, Hengyang City, Hunan Province, 421001, PR China.
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13
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Benchoula K, Mediani A, Hwa WE. The functions of Ca 2+/calmodulin-dependent protein kinase II (CaMKII) in diabetes progression. J Cell Commun Signal 2023; 17:25-34. [PMID: 35551607 PMCID: PMC10030766 DOI: 10.1007/s12079-022-00680-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 04/14/2022] [Indexed: 11/30/2022] Open
Abstract
The increase in blood glucose causes a myriad of pathways and molecular components to malfunction, leading to diabetes. Diabetes affects each organ differently by activating distinct pathways. It has an impact on the liver, pancreas, kidney (nephropathy), eyes (retinopathy), and nervous system (neuropathy). Understanding the effects of diabetes on each organ is the first step in developing a sustained treatment for the disease. Among the many cellular molecules impacted by diabetes is Ca2+/calmodulin-dependent protein kinase II (CaMKII), a complex Ca2+/calmodulin-activated serine/threonine-protein kinase. When intracellular [Ca2+] rises, it binds to calmodulin (CaM) to produce Ca2+/CaM, which activates CaMKIIs. This factor is involved in the pancreas, liver, heart, muscles, and various organs. Thus, Understanding CaMKII action in each organ is critical for gaining a complete picture of diabetic complications. Therefore, this review covers CaMKII's functions in many organs and how it affects and has been affected by diabetes.
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Affiliation(s)
- Khaled Benchoula
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, 1, Jalan Taylors, 47500, Subang Jaya, Selangor, Malaysia
| | - Ahmed Mediani
- Institute of Systems Biology (INBIOSIS), University Kebangsaan Malaysia, 43600, Bangi, Selangor, Malaysia
| | - Wong Eng Hwa
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, 1, Jalan Taylors, 47500, Subang Jaya, Selangor, Malaysia.
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14
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Yoon Y, Lee H, Federico M, Sheu SS. Non-conventional mitochondrial permeability transition: Its regulation by mitochondrial dynamics. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2023; 1864:148914. [PMID: 36063902 PMCID: PMC9729414 DOI: 10.1016/j.bbabio.2022.148914] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 07/21/2022] [Accepted: 08/29/2022] [Indexed: 11/21/2022]
Abstract
Mitochondrial permeability transition (MPT) is a phenomenon that the inner mitochondrial membrane (IMM) loses its selective permeability, leading to mitochondrial dysfunction and cell injury. Electrophysiological evidence indicates the presence of a mega-channel commonly called permeability transition pore (PTP) whose opening is responsible for MPT. However, the molecular identity of the PTP is still under intensive investigations and debates, although cyclophilin D that is inhibited by cyclosporine A (CsA) is the established regulatory component of the PTP. PTP can also open transiently and functions as a rapid mitochondrial Ca2+ releasing mechanism. Mitochondrial fission and fusion, the main components of mitochondrial dynamics, control the number and size of mitochondria, and have been shown to play a role in regulating MPT directly or indirectly. Studies by us and others have indicated the potential existence of a form of transient MPT that is insensitive to CsA. This "non-conventional" MPT is regulated by mitochondrial dynamics and may serve a protective role possibly by decreasing the susceptibility for a frequent or sustained PTP opening; hence, it may have a therapeutic value in many disease conditions involving MPT.
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Affiliation(s)
- Yisang Yoon
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta 30912, GA, USA.
| | - Hakjoo Lee
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta 30912, GA, USA
| | - Marilen Federico
- Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Shey-Shing Sheu
- Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
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15
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RCAN1 deficiency aggravates sepsis-induced cardiac remodeling and dysfunction by accelerating mitochondrial pathological fission. Inflamm Res 2022; 71:1589-1602. [DOI: 10.1007/s00011-022-01628-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/17/2022] [Accepted: 08/18/2022] [Indexed: 11/05/2022] Open
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16
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Tow BD, Deb A, Neupane S, Patel SM, Reed M, Loper AB, Eliseev RA, Knollmann BC, Györke S, Liu B. SR-Mitochondria Crosstalk Shapes Ca Signalling to Impact Pathophenotype in Disease Models Marked by Dysregulated Intracellular Ca Release. Cardiovasc Res 2022; 118:2819-2832. [PMID: 34677619 PMCID: PMC9724772 DOI: 10.1093/cvr/cvab324] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 10/12/2021] [Indexed: 12/29/2022] Open
Abstract
AIMS Diastolic Ca release (DCR) from sarcoplasmic reticulum (SR) Ca release channel ryanodine receptor (RyR2) has been linked to multiple cardiac pathologies, but its exact role in shaping divergent cardiac pathologies remains unclear. We hypothesize that the SR-mitochondria interplay contributes to disease phenotypes by shaping Ca signalling. METHODS AND RESULTS A genetic model of catecholaminergic polymorphic ventricular tachycardia (CPVT2 model of CASQ2 knockout) and a pre-diabetic cardiomyopathy model of fructose-fed mice (FFD), both marked by DCR, are employed in this study. Mitochondria Ca (mCa) is modulated by pharmacologically targeting mitochondria Ca uniporter (MCU) or permeability transition pore (mPTP), mCa uptake, and extrusion mechanisms, respectively. An MCU activator abolished Ca waves in CPVT2 but exacerbated waves in FFD cells. Mechanistically this is ascribed to mitochondria's function as a Ca buffer or source of reactive oxygen species (mtROS) to exacerbate RyR2 functionality, respectively. Enhancing mCa uptake reduced and elevated mtROS production in CPVT2 and FFD, respectively. In CPVT2, mitochondria took up more Ca in permeabilized cells, and had higher level of mCa content in intact cells vs. FFD. Conditional ablation of MCU in the CPVT2 model caused lethality and cardiac remodelling, but reduced arrhythmias in the FFD model. In parallel, CPVT2 mitochondria also employ up-regulated mPTP-mediated Ca efflux to avoid mCa overload, as seen by elevated incidence of MitoWinks (an indicator of mPTP-mediated Ca efflux) vs. FFD. Both pharmacological and genetic inhibition of mPTP promoted mtROS production and exacerbation of myocyte Ca handling in CPVT2. Further, genetic inhibition of mPTP exacerbated arrhythmias in CPVT2. CONCLUSION In contrast to FFD, which is more susceptible to mtROS-dependent RyR2 leak, in CPVT2 mitochondria buffer SR-derived DCR to mitigate Ca-dependent pathological remodelling and rely on mPTP-mediated Ca efflux to avoid mCa overload. SR-mitochondria interplay contributes to the divergent pathologies by disparately shaping intracellular Ca signalling.
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Affiliation(s)
- Brian D Tow
- Department of Biological Sciences, Mississippi State University, 295 Lee Blvd, Starkville, Mississippi, 39762, USA
| | - Arpita Deb
- Department of Biological Sciences, Mississippi State University, 295 Lee Blvd, Starkville, Mississippi, 39762, USA
| | - Shraddha Neupane
- Department of Biological Sciences, Mississippi State University, 295 Lee Blvd, Starkville, Mississippi, 39762, USA
| | - Shuchi M Patel
- Department of Biological Sciences, Mississippi State University, 295 Lee Blvd, Starkville, Mississippi, 39762, USA
| | - Meagan Reed
- Department of Biological Sciences, Mississippi State University, 295 Lee Blvd, Starkville, Mississippi, 39762, USA
| | - Anna-Beth Loper
- Department of Biological Sciences, Mississippi State University, 295 Lee Blvd, Starkville, Mississippi, 39762, USA
| | - Roman A Eliseev
- epartment of Orthopedics, Center for Musculoskeletal Research, University of Rochester, 601 Elmwood Ave, Rochester, New York 14624, USA
| | - Björn C Knollmann
- Department of Medicine, Vanderbilt University School of Medicine, 2215B Garland Ave, Nashville, Tennessee, 37232, USA
| | - Sándor Györke
- Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, The Ohio State University, 473 W. 12th Avenue, Columbus, Ohio 43210, USA
| | - Bin Liu
- Department of Biological Sciences, Mississippi State University, 295 Lee Blvd, Starkville, Mississippi, 39762, USA
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17
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Dabravolski SA, Sadykhov NK, Kartuesov AG, Borisov EE, Sukhorukov VN, Orekhov AN. The Role of Mitochondrial Abnormalities in Diabetic Cardiomyopathy. Int J Mol Sci 2022; 23:ijms23147863. [PMID: 35887211 PMCID: PMC9321738 DOI: 10.3390/ijms23147863] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic cardiomyopathy (DCM) is defined as the presence in diabetic patients of abnormal cardiac structure and performance (such as left ventricular hypertrophy, fibrosis, and arrhythmia) in the absence of other cardiac risk factors (such as hypertension or coronary artery disease). Although the pathogenesis of DCM remains unclear currently, mitochondrial structural and functional dysfunctions are recognised as a central player in the DCM development. In this review, we focus on the role of mitochondrial dynamics, biogenesis and mitophagy, Ca2+ metabolism and bioenergetics in the DCM development and progression. Based on the crucial role of mitochondria in DCM, application of mitochondria-targeting therapies could be effective strategies to slow down the progression of the disease.
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Affiliation(s)
- Siarhei A. Dabravolski
- Department of Clinical Diagnostics, Vitebsk State Academy of Veterinary Medicine [UO VGAVM], 7/11 Dovatora Str., 210026 Vitebsk, Belarus
- Correspondence:
| | - Nikolay K. Sadykhov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia; (N.K.S.); (A.G.K.)
| | - Andrey G. Kartuesov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia; (N.K.S.); (A.G.K.)
| | - Evgeny E. Borisov
- Petrovsky National Research Centre of Surgery, 2, Abrikosovsky Lane, 119991 Moscow, Russia; (E.E.B.); (V.N.S.)
| | - Vasily N. Sukhorukov
- Petrovsky National Research Centre of Surgery, 2, Abrikosovsky Lane, 119991 Moscow, Russia; (E.E.B.); (V.N.S.)
- Institute for Atherosclerosis Research, Osennyaya 4-1-207, 121609 Moscow, Russia;
| | - Alexander N. Orekhov
- Institute for Atherosclerosis Research, Osennyaya 4-1-207, 121609 Moscow, Russia;
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18
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Hua Y, Qian J, Cao J, Wang X, Zhang W, Zhang J. Ca2+/Calmodulin-Dependent Protein Kinase II Regulation by Inhibitor of Receptor Interacting Protein Kinase 3 Alleviates Necroptosis in Glycation End Products-Induced Cardiomyocytes Injury. Int J Mol Sci 2022; 23:ijms23136988. [PMID: 35805993 PMCID: PMC9266390 DOI: 10.3390/ijms23136988] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/18/2022] [Accepted: 06/20/2022] [Indexed: 01/27/2023] Open
Abstract
Necroptosisis a regulatory programmed form of necrosis. Receptor interacting protein kinase 3 (RIPK3) is a robust indicator of necroptosis. RIPK3 mediates myocardial necroptosis through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) in cardiac ischemia-reperfusion (I/R) injury and heart failure. However, the exact mechanism of RIPK3 in advanced glycation end products (AGEs)-induced cardiomyocytes necroptosis is not clear. In this study, cardiomyocytes were subjected to AGEs stimulation for 24 h. RIPK3 expression, CaMKII expression, and necroptosis were determined in cardiomyocytes after AGEs stimulation. Then, cardiomyocytes were transfected with RIPK3 siRNA to downregulate RIPK3 followed by AGEs stimulation for 24 h. CaMKIIδ alternative splicing, CaMKII activity, oxidative stress, necroptosis, and cell damage were detected again. Next, cardiomyocytes were pretreated with GSK′872, a specific RIPK3 inhibitor to assess whether it could protect cardiomyocytes against AGEs stimulation. We found that AGEs increased the expression of RIPK3, aggravated the disorder of CaMKII δ alternative splicing, promoted CaMKII activation, enhanced oxidative stress, induced necroptosis, and damaged cardiomyocytes. RIPK3 downregulation or RIPK3 inhibitor GSK′872 corrected CaMKIIδ alternative splicing disorder, inhibited CaMKII activation, reduced oxidative stress, attenuated necroptosis, and improved cell damage in cardiomyocytes.
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Affiliation(s)
- Yuyun Hua
- School of Pharmacy, Nantong University, Nantong 226001, China; (Y.H.); (J.Q.); (J.C.); (X.W.)
| | - Jianan Qian
- School of Pharmacy, Nantong University, Nantong 226001, China; (Y.H.); (J.Q.); (J.C.); (X.W.)
| | - Ji Cao
- School of Pharmacy, Nantong University, Nantong 226001, China; (Y.H.); (J.Q.); (J.C.); (X.W.)
| | - Xue Wang
- School of Pharmacy, Nantong University, Nantong 226001, China; (Y.H.); (J.Q.); (J.C.); (X.W.)
| | - Wei Zhang
- School of Pharmacy, Nantong University, Nantong 226001, China; (Y.H.); (J.Q.); (J.C.); (X.W.)
- School of Medicine, Nantong University, Nantong 226001, China
- Correspondence: (W.Z.); (J.Z.); Tel.: +86-513-8505-1726 (J.Z.); Fax: +86-513-8505-1728 (J.Z.)
| | - Jingjing Zhang
- School of Pharmacy, Nantong University, Nantong 226001, China; (Y.H.); (J.Q.); (J.C.); (X.W.)
- School of Medicine, Nantong University, Nantong 226001, China
- Correspondence: (W.Z.); (J.Z.); Tel.: +86-513-8505-1726 (J.Z.); Fax: +86-513-8505-1728 (J.Z.)
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19
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Cao J, Zhang J, Qian J, Wang X, Zhang W, Chen X. Ca 2+/Calmodulin-Dependent Protein Kinase II Regulation by RIPK3 Alleviates Necroptosis in Transverse Arch Constriction-Induced Heart Failure. Front Cardiovasc Med 2022; 9:847362. [PMID: 35571197 PMCID: PMC9097920 DOI: 10.3389/fcvm.2022.847362] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 04/11/2022] [Indexed: 12/24/2022] Open
Abstract
Some studies have reported that the activation of Ca2+/calmodulin dependent protein kinase (CaMKII) plays a vital role in the pathogenesis of cardiovascular disease. Moreover, receptor interacting protein kinase 3 (RIPK3)-mediated necroptosis is also involved in the pathological process of various heart diseases. In the present study, we aimed to investigate the effect of RIPK3-regulated CaMKII on necroptosis in heart failure (HF) and its underlying mechanism. Wild type (WT) and RIPK3-depleted (RIPK3–/–) mice were treated with transverse arch constriction (TAC). After 6 weeks, echocardiography, myocardial injury, CaMKII activity, necroptosis, RIPK3 expression, mixed lineage kinase domain-like protein (MLKL) phosphorylation, and mitochondrial ultrastructure were measured. The results showed that TAC aggravated cardiac dysfunction, CaMKII activation, and necroptosis in WT mice. However, depletion of RIPK3 alleviated cardiac insufficiency, CaMKII activation, and necroptosis in TAC-treated mice. To verify the experimental results, WT mice were transfected with AAV-vector and AAV-RIPK3 shRNA, followed by TAC operation. The findings were consistent with the expected results. Collectively, our current data indicated that the activation of CaMKII, MLKL and necroptosis in HF mice were increased in a RIPK3-dependent manner, providing valuable insights into the pathogenesis and treatment strategy of HF.
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Affiliation(s)
- Ji Cao
- School of Pharmacy, Nantong University, Nantong, China
| | - Jingjing Zhang
- School of Pharmacy, Nantong University, Nantong, China.,School of Medicine, Nantong University, Nantong, China
| | - Jianan Qian
- School of Pharmacy, Nantong University, Nantong, China
| | - Xue Wang
- School of Pharmacy, Nantong University, Nantong, China
| | - Wei Zhang
- School of Pharmacy, Nantong University, Nantong, China.,School of Medicine, Nantong University, Nantong, China
| | - Xiangfan Chen
- Department of Pharmacy, Nantong First People's Hospital, The Second Affiliated Hospital of Nantong University, Nantong, China
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20
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Consumption of combined fructose and sucrose diet exacerbates oxidative stress, hypertrophy and CaMKII δ oxidation in hearts from rats with metabolic syndrome. Mol Cell Biochem 2022; 477:1309-1320. [PMID: 35138512 DOI: 10.1007/s11010-022-04364-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 01/12/2022] [Indexed: 10/19/2022]
Abstract
The prevalence of the metabolic syndrome (MetS) and its cardiac comorbidities as cardiac hypertrophy (CH) have increased considerably due to the high consumption of carbohydrates, such as sucrose and/or fructose. We compared the effects of sucrose (S), fructose (F) and their combination (S + F) on the development of MetS in weaned male Wistar rats and established the relationship between the consumption of these sugars and the degree of cardiac CH development, oxidative stress (OS) and Calcium/calmodulin-dependent protein kinase type II subunit delta oxidation (ox-CaMKIIδ). 12 weeks after the beginning of treatments with S, F or S + F, arterial pressure was measured and 8 weeks later (to complete 20 weeks) the animals were sacrificed and blood samples, visceral adipose tissue and hearts were obtained. Biochemical parameters were determined in serum and cardiac tissue to evaluate the development of MetS and OS. To evaluate CH, atrial natriuretic peptide (ANP), CaMKIIδ and ox-CaMKIIδ were determined by western blot and histological studies were performed in cardiac tissue. Our data showed that chronic consumption of S + F exacerbates MetS-induced CH which is related with a higher OS and ox-CaMKIIδ.
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21
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Huang C, Du J, Ji B, Gong S, Geng C, Miao Y, Shen Q, Gu W, Wang L, Meng Q. The Eriocheir sinensis calcium/calmodulin-dependent protein kinase II activates apoptosis to resist Spiroplasma eriocheiris infection. FISH & SHELLFISH IMMUNOLOGY 2022; 121:223-231. [PMID: 34986398 DOI: 10.1016/j.fsi.2021.12.054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 12/21/2021] [Accepted: 12/29/2021] [Indexed: 06/14/2023]
Abstract
Calcium/calmodulin-dependent protein kinase II is a downstream mediator of calcium signalling and participates in the regulation of various cellular physiological functions. In previous studies, the expression of Eriocheir sinensis CaMKII (EsCaMKII) was significantly decreased in the thoracic ganglion after Spiroplasma eriocheiris infection, as shown using TMT-based quantitative proteomic analysis; however, the specific functions of EsCaMKII are still unclear. In this study, the full-length cDNA of EsCaMKII was 3314 bp long, consisting of a 1605 bp open reading frame encoding a protein of 535 amino acids, including a 258 aa serine/threonine protein kinase catalytic domain (EsCaMKII-CD). EsCaMKII is highly transcribed in haemocytes, nerves (thoracic ganglion), gills, and muscles, but lowly transcribed in the hepatopancreas, heart, and intestines. The transcription levels of EsCaMKII were altered in E. sinensis haemocytes after S. eriocheiris infection. After the over-expression of EsCaMKII-CD in RAW264.7 cells, the apoptosis rate of RAW264.7 cells was significantly increased. After the over-expression of EsCaMKII-CD, the morphology of RAW264.7 cells became worse after being infected with S. eriocheiris. Meanwhile, the copy number of S. eriocheiris in RAW264.7 cells was significantly decreased. From 48 h to 96 h after EsCaMKII RNA interference, the transcription levels of EsCaMKII decreased significantly. The transcription of apoptosis genes and cell apoptosis were also inhibited in haemocytes after EsCaMKII RNAi. The knockdown of EsCaMKII by RNAi resulted in significant increases in the copy number of S. eriocheiris and in the mortality of crabs during S. eriocheiris infection. These results indicate that EsCaMKII could promote the apoptosis of E. sinensis and enhance its ability to resist S. eriocheiris infection.
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Affiliation(s)
- Chen Huang
- Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Marine Science and Engineering, Nanjing Normal University, 2 Xuelin Road, Nanjing 210023, China
| | - Jie Du
- Animal Husbandry and Veterinary College, Jiangsu Vocational College of Agriculture and Forestry, Jurong, Jiangsu 212400, China
| | - Bairu Ji
- Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Marine Science and Engineering, Nanjing Normal University, 2 Xuelin Road, Nanjing 210023, China
| | - Sinan Gong
- Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Marine Science and Engineering, Nanjing Normal University, 2 Xuelin Road, Nanjing 210023, China
| | - Chao Geng
- Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Marine Science and Engineering, Nanjing Normal University, 2 Xuelin Road, Nanjing 210023, China
| | - Yanyang Miao
- Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Marine Science and Engineering, Nanjing Normal University, 2 Xuelin Road, Nanjing 210023, China
| | - Qingchun Shen
- Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Marine Science and Engineering, Nanjing Normal University, 2 Xuelin Road, Nanjing 210023, China
| | - Wei Gu
- Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Marine Science and Engineering, Nanjing Normal University, 2 Xuelin Road, Nanjing 210023, China
| | - Li Wang
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu, 610041, China.
| | - Qingguo Meng
- Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Marine Science and Engineering, Nanjing Normal University, 2 Xuelin Road, Nanjing 210023, China.
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22
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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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23
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Hegyi B, Ko CY, Bossuyt J, Bers DM. Two-hit mechanism of cardiac arrhythmias in diabetic hyperglycaemia: reduced repolarization reserve, neurohormonal stimulation, and heart failure exacerbate susceptibility. Cardiovasc Res 2021; 117:2781-2793. [PMID: 33483728 PMCID: PMC8683706 DOI: 10.1093/cvr/cvab006] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 01/10/2021] [Indexed: 12/11/2022] Open
Abstract
AIMS Diabetic hyperglycaemia is associated with increased arrhythmia risk. We aimed to investigate whether hyperglycaemia alone can be accountable for arrhythmias or whether it requires the presence of additional pathological factors. METHODS AND RESULTS Action potentials (APs) and arrhythmogenic spontaneous diastolic activities were measured in isolated murine ventricular, rabbit atrial, and ventricular myocytes acutely exposed to high glucose. Acute hyperglycaemia increased the short-term variability (STV) of action potential duration (APD), enhanced delayed afterdepolarizations, and the inducibility of APD alternans during tachypacing in both murine and rabbit atrial and ventricular myocytes. Hyperglycaemia also prolonged APD in mice and rabbit atrial cells but not in rabbit ventricular myocytes. However, rabbit ventricular APD was more strongly depressed by block of late Na+ current (INaL) during hyperglycaemia, consistent with elevated INaL in hyperglycaemia. All the above proarrhythmic glucose effects were Ca2+-dependent and abolished by CaMKII inhibition. Importantly, when the repolarization reserve was reduced by pharmacological inhibition of K+ channels (either Ito, IKr, IKs, or IK1) or hypokalaemia, acute hyperglycaemia further prolonged APD and further increased STV and alternans in rabbit ventricular myocytes. Likewise, when rabbit ventricular myocytes were pretreated with isoproterenol or angiotensin II, hyperglycaemia significantly prolonged APD, increased STV and promoted alternans. Moreover, acute hyperglycaemia markedly prolonged APD and further enhanced STV in failing rabbit ventricular myocytes. CONCLUSION We conclude that even though hyperglycaemia alone can enhance cellular proarrhythmic mechanisms, a second hit which reduces the repolarization reserve or stimulates G protein-coupled receptor signalling greatly exacerbates cardiac arrhythmogenesis in diabetic hyperglycaemia.
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Affiliation(s)
- Bence Hegyi
- Department of Pharmacology, University of California, Davis, 451 Health Sciences Drive, CA 95616, USA
| | - Christopher Y Ko
- Department of Pharmacology, University of California, Davis, 451 Health Sciences Drive, CA 95616, USA
| | - Julie Bossuyt
- Department of Pharmacology, University of California, Davis, 451 Health Sciences Drive, CA 95616, USA
| | - Donald M Bers
- Department of Pharmacology, University of California, Davis, 451 Health Sciences Drive, CA 95616, USA
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24
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Gaitán-González P, Sánchez-Hernández R, Arias-Montaño JA, Rueda A. Tale of two kinases: Protein kinase A and Ca 2+/calmodulin-dependent protein kinase II in pre-diabetic cardiomyopathy. World J Diabetes 2021; 12:1704-1718. [PMID: 34754372 PMCID: PMC8554373 DOI: 10.4239/wjd.v12.i10.1704] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 07/28/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Metabolic syndrome is a pre-diabetic state characterized by several biochemical and physiological alterations, including insulin resistance, visceral fat accumulation, and dyslipidemias, which increase the risk for developing cardiovascular disease. Metabolic syndrome is associated with augmented sympathetic tone, which could account for the etiology of pre-diabetic cardiomyopathy. This review summarizes the current knowledge of the pathophysiological consequences of enhanced and sustained β-adrenergic response in pre-diabetes, focusing on cardiac dysfunction reported in diet-induced experimental models of pre-diabetic cardiomyopathy. The research reviewed indicates that both protein kinase A and Ca2+/calmodulin-dependent protein kinase II play important roles in functional responses mediated by β1-adrenoceptors; therefore, alterations in the expression or function of these kinases can be deleterious. This review also outlines recent information on the role of protein kinase A and Ca2+/calmodulin-dependent protein kinase II in abnormal Ca2+ handling by cardiomyocytes from diet-induced models of pre-diabetic cardiomyopathy.
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Affiliation(s)
- Pamela Gaitán-González
- Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México 07360, Mexico
| | - Rommel Sánchez-Hernández
- Department of Physiology, Biophysics and Neurosciences, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México 07360, Mexico
| | - José-Antonio Arias-Montaño
- Department of Physiology, Biophysics and Neurosciences, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México 07360, Mexico
| | - Angélica Rueda
- Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México 07360, Mexico
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25
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Ni L, Lahiri SK, Nie J, Pan X, Abu-Taha I, Reynolds JO, Campbell HM, Wang H, Kamler M, Schmitz W, Müller FU, Li N, Wei X, Wang DW, Dobrev D, Wehrens XHT. Genetic inhibition of Nuclear Factor of Activated T-cell c2 (NFATc2) prevents atrial fibrillation in CREM transgenic mice. Cardiovasc Res 2021; 118:2805-2818. [PMID: 34648001 PMCID: PMC9586567 DOI: 10.1093/cvr/cvab325] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 10/11/2021] [Indexed: 11/14/2022] Open
Abstract
AIMS Abnormal intracellular calcium handling contributes to the progressive nature of atrial fibrillation (AF), the most common sustained cardiac arrhythmia. Evidence in mouse models suggests that activation of the nuclear factor of activated T-cell (NFAT) signaling pathway contributes to atrial remodeling. Our aim was to determine the role of NFATc2 in AF in humans and mouse models. METHODS AND RESULTS Expression levels of NFATc1-c4 isoforms were assessed by quantitative reverse transcription-polymerase chain reaction in right atrial appendages from patients with chronic AF. NFATc1 and NFATc2 mRNA levels were elevated in chronic AF (cAF) patients compared with those in sinus rhythm (SR). Western blotting revealed increased cytosolic and nuclear levels of NFATc2 in AF patients. Similar findings were obtained in CREM-IbΔC-X transgenic (CREM) mice, a model of progressive AF. Telemetry ECG recordings revealed age-dependent spontaneous AF in CREM mice, which was prevented by NFATc2 knockout in CREM: NFATc2-/- mice. Programmed electrical stimulation revealed that CREM: NFATc2-/- mice lacked an AF substrate. Morphometric analysis and histology revealed increased atrial weight and atrial fibrosis in CREM mice compared with WT controls, which was reversed in CREM: NFATc2-/- mice. Confocal microscopy showed an increased Ca2+ spark frequency despite a reduced sarcoplasmic reticulum (SR) Ca2+ load in CREM mice compared with controls, whereas these abnormalities were normalized in CREM: NFATc2-/- mice. Western blotting revealed that genetic inhibition of Ca2+/calmodulin-dependent protein kinase II-mediated phosphorylation of S2814 on RyR2 in CREM: RyR2-S2814A mice suppressed NFATc2 activation observed in CREM mice, suggesting that NFATc2 is activated by excessive SR Ca2+ leak via RyR2. Finally, chromatin immunoprecipitation sequencing from AF patients identified Ras And EF-Hand Domain-Containing Protein (RASEF) as a direct target of NFATc2 mediated transcription. CONCLUSION Our findings reveal activation of the NFAT signaling pathway in patients of Chinese and European descent. NFATc2 knockout prevents the progression of AF in the CREM mouse model. TRANSLATIONAL PERSPECTIVE Atrial fibrillation (AF) is a progressive disease characterized by electrical and structural remodeling which promotes atrial arrhythmias. This study provides evidence for increased 'nuclear factor of activated T-cell' (NFAT) signaling in patients with chronic AF. Studies in the CREM transgenic model of progressive AF revealed that the NFATc2 isoform mediates atrial remodeling associated with AF substrate development. Chromatin immunoprecipitation sequencing of atrial biopsies from AF patients identified 'Ras And EF-Hand Domain-Containing Protein' (RASEF) as a downstream target of NFATc2-mediated transcription, suggesting that targeting these factors might be beneficial for curtailing AF progression.
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Affiliation(s)
- Li Ni
- Division of Cardiology, Department of Internal Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Satadru K Lahiri
- Cardiovascular Research Institute.,Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA
| | - Jiali Nie
- Division of Cardiology, Department of Internal Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Xiaolu Pan
- Cardiovascular Research Institute.,Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA
| | - Issam Abu-Taha
- Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany
| | - Julia O Reynolds
- Cardiovascular Research Institute.,Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA
| | - Hannah M Campbell
- Cardiovascular Research Institute.,Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA
| | - Haihao Wang
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Markus Kamler
- Cardiac Surgery II Essen-Huttrop, University Hospital, West German Heart Center, University of Essen, Germany
| | - Wilhelm Schmitz
- Institute of Pharmacology and Toxicology, University of Münster, Germany
| | | | - Na Li
- Cardiovascular Research Institute.,Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA.,Institute of Pharmacology and Toxicology, University of Münster, Germany
| | - Xiang Wei
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Dobromir Dobrev
- Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany
| | - Xander H T Wehrens
- Cardiovascular Research Institute.,Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA.,Department of Medicine (Section of Cardiovascular Research), Baylor College of Medicine, Houston, TX, 77030 USA.,Department of Medicine (Cardiology), Baylor College of Medicine, Houston, TX, 77030 USA.,Department of Pediatrics, Center for Space Medicine, Baylor College of Medicine, Houston, TX, 77030 USA
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26
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Federico M, Zavala M, Vico T, López S, Portiansky E, Alvarez S, Abrille MCV, Palomeque J. CaMKII activation in early diabetic hearts induces altered sarcoplasmic reticulum-mitochondria signaling. Sci Rep 2021; 11:20025. [PMID: 34625584 PMCID: PMC8501049 DOI: 10.1038/s41598-021-99118-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 07/20/2021] [Indexed: 01/01/2023] Open
Abstract
Prediabetic myocardium, induced by fructose-rich diet (FRD), is prone to increased sarcoplasmic reticulum (SR)-Ca2+ leak and arrhythmias due to increased activity of the Ca2+/calmodulin protein kinase II (CaMKII). However, little is known about the role of SR-mitochondria microdomains, mitochondrial structure, and mitochondrial metabolisms. To address this knowledge gap we measured SR-mitochondrial proximity, intracellular Ca2+, and mitochondrial metabolism in wild type (WT) and AC3-I transgenic mice, with myocardial-targeted CaMKII inhibition, fed with control diet (CD) or with FRD. Confocal images showed significantly increased spontaneous Ca2+ release events in FRD vs. CD WT cardiomyocytes. [3H]-Ryanodine binding assay revealed higher [3H]Ry binding in FRD than CD WT hearts. O2 consumption at State 4 and hydrogen peroxide (H2O2) production rate were increased, while respiratory control rate (RCR) and Ca2+ retention capacity (CRC) were decreased in FRD vs. CD WT isolated mitochondria. Transmission Electron Microscopy (TEM) images showed increased proximity at the SR-mitochondria microdomains, associated with increased tethering proteins, Mfn2, Grp75, and VDAC in FRD vs. CD WT. Mitochondria diameter was decrease and roundness and density were increased in FRD vs. CD WT specimens. The fission protein, Drp1 was significantly increased while the fusion protein, Opa1 was unchanged in FRD vs. CD WT hearts. These differences were prevented in AC3-I mice. We conclude that SR-mitochondria microdomains are subject to CaMKII-dependent remodeling, involving SR-Ca2+ leak and mitochondria fission, in prediabetic mice induced by FRD. We speculate that CaMKII hyperactivity induces SR-Ca2+ leak by RyR2 activation which in turn increases mitochondria Ca2+ content due to the enhanced SR-mitochondria tethering, decreasing CRC.
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Affiliation(s)
- Marilen Federico
- Centro de Investigaciones Cardiovasculares, UNLP-CONICET-CCT La Plata, Facultad de Ciencias Médicas, UNLP, 60 y 120 s/n, La Plata, CP 1900, Argentina
| | - Maite Zavala
- Centro de Investigaciones Cardiovasculares, UNLP-CONICET-CCT La Plata, Facultad de Ciencias Médicas, UNLP, 60 y 120 s/n, La Plata, CP 1900, Argentina
| | - Tamara Vico
- Instituto de Bioquímica y Medicina Molecular, UBA-CONICET, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina
| | - Sofía López
- Centro de Investigaciones Cardiovasculares, UNLP-CONICET-CCT La Plata, Facultad de Ciencias Médicas, UNLP, 60 y 120 s/n, La Plata, CP 1900, Argentina
| | - Enrique Portiansky
- Laboratorio de Análisis de Imágenes, UNLP, Facultad de Ciencias Veterinarias, La Plata, Argentina
| | - Silvia Alvarez
- Instituto de Bioquímica y Medicina Molecular, UBA-CONICET, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina
| | - Maria Celeste Villa Abrille
- Centro de Investigaciones Cardiovasculares, UNLP-CONICET-CCT La Plata, Facultad de Ciencias Médicas, UNLP, 60 y 120 s/n, La Plata, CP 1900, Argentina
| | - Julieta Palomeque
- Centro de Investigaciones Cardiovasculares, UNLP-CONICET-CCT La Plata, Facultad de Ciencias Médicas, UNLP, 60 y 120 s/n, La Plata, CP 1900, Argentina.
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27
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Veitch CR, Power AS, Erickson JR. CaMKII Inhibition is a Novel Therapeutic Strategy to Prevent Diabetic Cardiomyopathy. Front Pharmacol 2021; 12:695401. [PMID: 34381362 PMCID: PMC8350113 DOI: 10.3389/fphar.2021.695401] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/14/2021] [Indexed: 11/24/2022] Open
Abstract
Increasing prevalence of diabetes mellitus worldwide has pushed the complex disease state to the foreground of biomedical research, especially concerning its multifaceted impacts on the cardiovascular system. Current therapies for diabetic cardiomyopathy have had a positive impact, but with diabetic patients still suffering from a significantly greater burden of cardiac pathology compared to the general population, the need for novel therapeutic approaches is great. A new therapeutic target, calcium/calmodulin-dependent kinase II (CaMKII), has emerged as a potential treatment option for preventing cardiac dysfunction in the setting of diabetes. Within the last 10 years, new evidence has emerged describing the pathophysiological consequences of CaMKII activation in the diabetic heart, the mechanisms that underlie persistent CaMKII activation, and the protective effects of CaMKII inhibition to prevent diabetic cardiomyopathy. This review will examine recent evidence tying cardiac dysfunction in diabetes to CaMKII activation. It will then discuss the current understanding of the mechanisms by which CaMKII activity is enhanced during diabetes. Finally, it will examine the benefits of CaMKII inhibition to treat diabetic cardiomyopathy, including contractile dysfunction, heart failure with preserved ejection fraction, and arrhythmogenesis. We intend this review to serve as a critical examination of CaMKII inhibition as a therapeutic strategy, including potential drawbacks of this approach.
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Affiliation(s)
- Christopher R Veitch
- Department of Physiology and HeartOtago, University of Otago, Dunedin, New Zealand
| | - Amelia S Power
- Department of Physiology and HeartOtago, University of Otago, Dunedin, New Zealand
| | - Jeffrey R Erickson
- Department of Physiology and HeartOtago, University of Otago, Dunedin, New Zealand
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28
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Federico M, De la Fuente S, Palomeque J, Sheu SS. The role of mitochondria in metabolic disease: a special emphasis on heart dysfunction. J Physiol 2021; 599:3477-3493. [PMID: 33932959 PMCID: PMC8424986 DOI: 10.1113/jp279376] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 03/18/2021] [Indexed: 01/10/2023] Open
Abstract
Metabolic diseases (MetDs) embrace a series of pathologies characterized by abnormal body glucose usage. The known diseases included in this group are metabolic syndrome, prediabetes and diabetes mellitus types 1 and 2. All of them are chronic pathologies that present metabolic disturbances and are classified as multi-organ diseases. Cardiomyopathy has been extensively described in diabetic patients without overt macrovascular complications. The heart is severely damaged during the progression of the disease; in fact, diabetic cardiomyopathies are the main cause of death in MetDs. Insulin resistance, hyperglycaemia and increased free fatty acid metabolism promote cardiac damage through mitochondria. These organelles supply most of the energy that the heart needs to beat and to control essential cellular functions, including Ca2+ signalling modulation, reactive oxygen species production and apoptotic cell death regulation. Several aspects of common mitochondrial functions have been described as being altered in diabetic cardiomyopathies, including impaired energy metabolism, compromised mitochondrial dynamics, deficiencies in Ca2+ handling, increases in reactive oxygen species production, and a higher probability of mitochondrial permeability transition pore opening. Therefore, the mitochondrial role in MetD-mediated heart dysfunction has been studied extensively to identify potential therapeutic targets for improving cardiac performance. Herein we review the cardiac pathology in metabolic syndrome, prediabetes and diabetes mellitus, focusing on the role of mitochondrial dysfunctions.
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Affiliation(s)
- Marilen Federico
- Centro de Investigaciones Cardiovasculares, CCT-La Plata-CONICET, Facultad de Cs. Medicas, UNLP, La Plata, Argentina
| | - Sergio De la Fuente
- Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107 USA
| | - Julieta Palomeque
- Centro de Investigaciones Cardiovasculares, CCT-La Plata-CONICET, Facultad de Cs. Medicas, UNLP, La Plata, Argentina
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, CABA, Argentina
| | - Shey-Shing Sheu
- Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107 USA
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29
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Cheng WL, Li SJ, Lee TI, Lee TW, Chung CC, Kao YH, Chen YJ. Sugar Fructose Triggers Gut Dysbiosis and Metabolic Inflammation with Cardiac Arrhythmogenesis. Biomedicines 2021; 9:728. [PMID: 34201938 PMCID: PMC8301417 DOI: 10.3390/biomedicines9070728] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/11/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023] Open
Abstract
Fructose is a main dietary sugar involved in the excess sugar intake-mediated progression of cardiovascular diseases and cardiac arrhythmias. Chronic intake of fructose has been the focus on the possible contributor to the metabolic diseases and cardiac inflammation. Recently, the small intestine was identified to be a major organ in fructose metabolism. The overconsumption of fructose induces dysbiosis of the gut microbiota, which, in turn, increases intestinal permeability and activates host inflammation. Endotoxins and metabolites of the gut microbiota, such as lipopolysaccharide, trimethylamine N-oxide, and short-chain fatty acids, also influence the host inflammation and cardiac biofunctions. Thus, high-fructose diets cause heart-gut axis disorders that promote cardiac arrhythmia. Understanding how gut microbiota dysbiosis-mediated inflammation influences the pathogenesis of cardiac arrhythmia may provide mechanisms for cardiac arrhythmogenesis. This narrative review updates our current understanding of the roles of excessive intake of fructose on the heart-gut axis and proposes potential strategies for inflammation-associated cardiac vascular diseases.
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Affiliation(s)
- Wan-Li Cheng
- Division of Cardiovascular Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; (W.-L.C.); (S.-J.L.)
- Division of Cardiovascular Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan;
| | - Shao-Jung Li
- Division of Cardiovascular Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; (W.-L.C.); (S.-J.L.)
- Division of Cardiovascular Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan;
| | - 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
- Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, 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
| | - Cheng-Chih Chung
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan;
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
| | - Yu-Hsun Kao
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan;
- 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
| | - Yi-Jen Chen
- Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan;
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
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Chiang DY, Lahiri S, Wang G, Karch J, Wang MC, Jung SY, Heck AJR, Scholten A, Wehrens XHT. Phosphorylation-Dependent Interactome of Ryanodine Receptor Type 2 in the Heart. Proteomes 2021; 9:proteomes9020027. [PMID: 34200203 PMCID: PMC8293434 DOI: 10.3390/proteomes9020027] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 05/27/2021] [Accepted: 06/02/2021] [Indexed: 11/16/2022] Open
Abstract
Hyperphosphorylation of the calcium release channel/ryanodine receptor type 2 (RyR2) at serine 2814 (S2814) is associated with multiple cardiac diseases including atrial fibrillation and heart failure. Despite recent advances, the molecular mechanisms driving pathological changes associated with RyR2 S2814 phosphorylation are still not well understood. Methods: Using affinity-purification coupled to mass spectrometry (AP-MS), we investigated the RyR2 interactome in ventricles from wild-type (WT) mice and two S2814 knock-in mutants: the unphosphorylated alanine mutant (S2814A) and hyperphosphorylated mimic aspartic acid mutant (S2814D). Western blots were used for validation. Results: In WT mouse ventricular lysates, we identified 22 proteins which were enriched with RyR2 pull-down relative to both IgG control and no antibody (beads-only) pull-downs. Parallel AP-MS using WT, S2814A, and S2814D mouse ventricles identified 72 proteins, with 20 being high confidence RyR2 interactors. Of these, 14 had an increase in their binding to RyR2 S2814A but a decrease in their binding to RyR2 S2814D. We independently validated three protein hits, Idh3b, Aifm1, and Cpt1b, as RyR2 interactors by western blots and showed that Aifm1 and Idh3b had significantly decreased binding to RyR2 S2814D compared to WT and S2814A, consistent with MS findings. Conclusion: By applying state-of-the-art proteomic approaches, we discovered a number of novel RyR2 interactors in the mouse heart. In addition, we found and defined specific alterations in the RyR2 interactome that were dependent on the phosphorylation status of RyR2 at S2814. These findings yield mechanistic insights into RyR2 regulation which may guide future drug designs.
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Affiliation(s)
- David Y. Chiang
- Cardiovascular Division, Department of Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA 02115, USA;
| | - Satadru Lahiri
- Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; (S.L.); (G.W.); (J.K.)
- Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Guoliang Wang
- Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; (S.L.); (G.W.); (J.K.)
| | - Jason Karch
- Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; (S.L.); (G.W.); (J.K.)
- Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Meng C. Wang
- Huffington Center on Aging, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA;
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sung Y. Jung
- Department of Biochemistry, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Albert J. R. Heck
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 Utrecht, The Netherlands; (A.J.R.H.); (A.S.)
- Netherlands Proteomics Centre, 3584 Utrecht, The Netherlands
| | - Arjen Scholten
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 Utrecht, The Netherlands; (A.J.R.H.); (A.S.)
- Netherlands Proteomics Centre, 3584 Utrecht, The Netherlands
| | - Xander H. T. Wehrens
- Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; (S.L.); (G.W.); (J.K.)
- Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Medicine (Cardiology), Baylor College of Medicine, Houston, TX 77030, USA
- Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston, TX 77030, USA
- Center for Space Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Correspondence: ; Tel.: +1-713-798-4261
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31
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Barteková M, Adameová A, Görbe A, Ferenczyová K, Pecháňová O, Lazou A, Dhalla NS, Ferdinandy P, Giricz Z. Natural and synthetic antioxidants targeting cardiac oxidative stress and redox signaling in cardiometabolic diseases. Free Radic Biol Med 2021; 169:446-477. [PMID: 33905865 DOI: 10.1016/j.freeradbiomed.2021.03.045] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/22/2021] [Accepted: 03/25/2021] [Indexed: 12/12/2022]
Abstract
Cardiometabolic diseases (CMDs) are metabolic diseases (e.g., obesity, diabetes, atherosclerosis, rare genetic metabolic diseases, etc.) associated with cardiac pathologies. Pathophysiology of most CMDs involves increased production of reactive oxygen species and impaired antioxidant defense systems, resulting in cardiac oxidative stress (OxS). To alleviate OxS, various antioxidants have been investigated in several diseases with conflicting results. Here we review the effect of CMDs on cardiac redox homeostasis, the role of OxS in cardiac pathologies, as well as experimental and clinical data on the therapeutic potential of natural antioxidants (including resveratrol, quercetin, curcumin, vitamins A, C, and E, coenzyme Q10, etc.), synthetic antioxidants (including N-acetylcysteine, SOD mimetics, mitoTEMPO, SkQ1, etc.), and promoters of antioxidant enzymes in CMDs. As no antioxidant indicated for the prevention and/or treatment of CMDs has reached the market despite the large number of preclinical and clinical studies, a sizeable translational gap is evident in this field. Thus, we also highlight potential underlying factors that may contribute to the failure of translation of antioxidant therapies in CMDs.
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Affiliation(s)
- Monika Barteková
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, 84104 Bratislava, Slovakia; Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, 81372 Bratislava, Slovakia.
| | - Adriana Adameová
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, 84104 Bratislava, Slovakia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, 83232 Bratislava, Slovakia
| | - Anikó Görbe
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1085 Budapest, Hungary; Pharmahungary Group, 6722 Szeged, Hungary
| | - Kristína Ferenczyová
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, 84104 Bratislava, Slovakia
| | - Oľga Pecháňová
- Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, 81371 Bratislava, Slovakia
| | - Antigone Lazou
- Laboratory of Animal Physiology, School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Naranjan S Dhalla
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, And Department of Physiology & Pathophysiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0W2, Canada
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1085 Budapest, Hungary; Pharmahungary Group, 6722 Szeged, Hungary
| | - Zoltán Giricz
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1085 Budapest, Hungary; Pharmahungary Group, 6722 Szeged, Hungary
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32
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Sepúlveda M, Burgos JI, Ciocci Pardo A, González Arbelaez L, Mosca S, Vila Petroff M. CaMKII-dependent ryanodine receptor phosphorylation mediates sepsis-induced cardiomyocyte apoptosis. J Cell Mol Med 2021; 24:9627-9637. [PMID: 33460250 PMCID: PMC7520277 DOI: 10.1111/jcmm.15470] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 05/01/2020] [Accepted: 05/12/2020] [Indexed: 11/27/2022] Open
Abstract
Sepsis is associated with cardiac dysfunction, which is at least in part due to cardiomyocyte apoptosis. However, the underlying mechanisms are far from being understood. Using the colon ascendens stent peritonitis mouse model of sepsis (CASP), we examined the subcellular mechanisms that mediate sepsis‐induced apoptosis. Wild‐type (WT) CASP mice hearts showed an increase in apoptosis respect to WT‐Sham. CASP transgenic mice expressing a CaMKII inhibitory peptide (AC3‐I) were protected against sepsis‐induced apoptosis. Dantrolene, used to reduce ryanodine receptor (RyR) diastolic sarcoplasmic reticulum (SR) Ca2+ release, prevented apoptosis in WT‐CASP. To examine whether CaMKII‐dependent RyR2 phosphorylation mediates diastolic Ca2+ release and apoptosis in sepsis, we evaluated apoptosis in mutant mice hearts that have the CaMKII phosphorylation site of RyR2 (Serine 2814) mutated to Alanine (S2814A). S2814A CASP mice did not show increased apoptosis. Consistent with RyR2 phosphorylation‐dependent enhancement in diastolic SR Ca2+ release leading to mitochondrial Ca2+ overload, mitochondrial Ca2+ retention capacity was reduced in mitochondria isolated from WT‐CASP compared to Sham and this reduction was absent in mitochondria from CASP S2814A or dantrolene‐treated mice. We conclude that in sepsis, CaMKII‐dependent RyR2 phosphorylation results in diastolic Ca2+ release from SR which leads to mitochondrial Ca2+ overload and apoptosis.
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Affiliation(s)
- Marisa Sepúlveda
- Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Juan Ignacio Burgos
- Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Alejandro Ciocci Pardo
- Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Luisa González Arbelaez
- Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Susana Mosca
- Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Martin Vila Petroff
- Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina
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33
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Gowen BH, Reyes MV, Joseph LC, Morrow JP. Mechanisms of Chronic Metabolic Stress in Arrhythmias. Antioxidants (Basel) 2020; 9:antiox9101012. [PMID: 33086602 PMCID: PMC7603089 DOI: 10.3390/antiox9101012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 10/07/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
Cardiac arrhythmias are responsible for many cardiovascular disease-related deaths worldwide. While arrhythmia pathogenesis is complex, there is increasing evidence for metabolic causes. Obesity, diabetes, and chronically consuming high-fat foods significantly increase the likelihood of developing arrhythmias. Although these correlations are well established, mechanistic explanations connecting a high-fat diet (HFD) to arrhythmogenesis are incomplete, although oxidative stress appears to be critical. This review investigates the metabolic changes that occur in obesity and after HFD. Potential therapies to prevent or treat arrhythmias are discussed, including antioxidants.
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Affiliation(s)
| | | | | | - John P. Morrow
- Correspondence: ; Tel.: +1-212-305-5553; Fax: +1-212-305-4648
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34
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Sphingosylphosphorylcholine alleviates hypoxia-caused apoptosis in cardiac myofibroblasts via CaM/p38/STAT3 pathway. Apoptosis 2020; 25:853-863. [DOI: 10.1007/s10495-020-01639-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/03/2020] [Indexed: 12/21/2022]
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35
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Silencing circ_0062389 alleviates cardiomyocyte apoptosis in heart failure rats via modulating TGF-β1/Smad3 signaling pathway. Gene 2020; 766:145154. [PMID: 32949699 DOI: 10.1016/j.gene.2020.145154] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/31/2020] [Accepted: 09/11/2020] [Indexed: 02/06/2023]
Abstract
CircRNA serves a crucial role in the development of heart failure (HF). Nevertheless, the regulatory mechanisms of circ_0062389 in HF are unknown. This study aims to examine the effect and mechanism of circ_0062389 on cardiomyocyte apoptosis in HF rats and H9C2 cells. Rats were divided into 5 groups (n = 8/group): the Control group, Sham group, HF group, HF + si-NC group, and HF + si-circRNA group. The echocardiography was used to examine the cardiac function, including LVIDd, LVIDs, IVSd, and IVSs. The apoptosis of myocardial tissue was detected through TUNEL method. H9C2 cells were randomly assigned into Control group (untransfected H9C2 cells), H/R group (untransfected H/R H9C2 cells), H/R + si-NC group (transfected si-NC) and H/R + si-circRNA group (transfect si-circ_0062389). Cell apoptosis was assessed through flow cytometry. The expression of circ_0062389 in myocardial tissues of HF rats was significantly higher than that of Control group and Sham group. Silencing circ_0062389 significantly reduced the levels of LVIDd, LVIDs, IVSd, and IVSs. Additionally, silencing circ_0062389 could significantly reduce the apoptosis rate of rat cardiomyocytes. Besides, silencing circ_0062389 significantly reduced the expression of TGF-β1 and Smad3 protein. Silencing circ_0062389 could alleviate cardiomyocyte apoptosis in HF rats via modulating TGF-β1/Smad3 signaling pathway, which might be a promising target for the treatment of HF.
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36
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Romero-García T, Landa-Galvan HV, Pavón N, Mercado-Morales M, Valdivia HH, Rueda A. Autonomous activation of CaMKII exacerbates diastolic calcium leak during beta-adrenergic stimulation in cardiomyocytes of metabolic syndrome rats. Cell Calcium 2020; 91:102267. [PMID: 32920522 DOI: 10.1016/j.ceca.2020.102267] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 08/05/2020] [Accepted: 08/05/2020] [Indexed: 02/06/2023]
Abstract
Autonomous Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation induces abnormal diastolic Ca2+ leak, which leads to triggered arrhythmias in a wide range of cardiovascular diseases, including diabetic cardiomyopathy. In hyperglycemia, Ca2+ handling alterations can be aggravated under stress conditions via the β-adrenergic signaling pathway, which also involves CaMKII activation. However, little is known about intracellular Ca2+ handling disturbances under β-adrenergic stimulation in cardiomyocytes of the prediabetic metabolic syndrome (MetS) model with obesity, and the participation of CaMKII in these alterations. MetS was induced in male Wistar rats by administering 30 % sucrose in drinking water for 16 weeks. Fluo 3-loaded MetS cardiomyocytes exhibited augmented diastolic Ca2+ leak (in the form of spontaneous Ca2+ waves) under basal conditions and that Ca2+ leakage was exacerbated by isoproterenol (ISO, 100 nM). At the molecular level, [3H]-ryanodine binding and basal phosphorylation of cardiac ryanodine receptor (RyR2) at Ser2814, a CaMKII site, were increased in heart homogenates of MetS rats with no changes in RyR2 expression. These alterations were not further augmented by Isoproterenol. SERCA pump activity was augmented 48 % in MetS hearts before β-adrenergic stimuli, which is associated to augmented PLN phosphorylation at T17, a target of CaMKII. In MetS hearts. CaMKII auto-phosphorylation (T287) was increased by 80 %. The augmented diastolic Ca2+ leak was prevented by CaMKII inhibition with AIP. In conclusion, CaMKII autonomous activation in cardiomyocytes of MetS rats with central obesity significantly contributes to abnormal diastolic Ca2+ leak, increasing the propensity for β-adrenergic receptor-driven lethal arrhythmias.
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Affiliation(s)
- Tatiana Romero-García
- Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del IPN, Cinvestav-IPN, Mexico City, 07300 Mexico
| | - Huguet V Landa-Galvan
- Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del IPN, Cinvestav-IPN, Mexico City, 07300 Mexico
| | - Natalia Pavón
- Department of Pharmacology, Instituto Nacional de Cardiología "Ignacio Chavez", Mexico City, Mexico
| | - Martha Mercado-Morales
- Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del IPN, Cinvestav-IPN, Mexico City, 07300 Mexico
| | - Héctor H Valdivia
- Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA
| | - Angélica Rueda
- Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del IPN, Cinvestav-IPN, Mexico City, 07300 Mexico.
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Burgos JI, Morell M, Mariángelo JIE, Vila Petroff M. Hyperosmotic stress promotes endoplasmic reticulum stress-dependent apoptosis in adult rat cardiac myocytes. Apoptosis 2020; 24:785-797. [PMID: 31309362 DOI: 10.1007/s10495-019-01558-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In different pathological situations, cardiac cells undergo hyperosmotic stress and cell shrinkage. This change in cellular volume has been associated with contractile dysfunction and cell death. However, the intracellular mechanisms involved in hyperosmotic stress-induced cell death have not been investigated in depth in adult cardiac myocytes. Given that osmotic stress has been shown to promote endoplasmic reticulum stress (ERS), a recognized trigger for apoptosis, we examined whether hyperosmotic stress triggers ERS in adult cardiac myocytes and if so whether this mechanism mediates hyperosmotic stress-induced cell death. Adult rat cardiomyocytes cultured overnight in a hypertonic solution (HS) containing mannitol as the osmolite, showed increased expression of ERS markers, GRP78, CHOP and cleaved-Caspase-12, compared with myocytes in isotonic solution (IS), suggesting that hyperosmotic stress induces ERS. In addition, HS significantly reduced cell viability and increased TUNEL staining and the expression of active Caspase-3, indicative of apoptosis. These effects were prevented with the addition of the ERS inhibitor, 4-PBA, indicating that hyperosmotic stress-induced apoptosis is mediated by ERS. Hyperosmotic stress-induced apoptosis was also prevented when cells were cultured in the presence of a Ca2+-chelating agent (EGTA) or the CaMKII inhibitor (KN93), suggesting that hyperosmotic stress-induced ERS is mediated by a Ca2+ and CaMKII-dependent mechanism. Similar results were observed when hyperosmotic stress was induced using glucose as the osmolite. We conclude that hyperosmotic stress promotes ERS by a CaMKII-dependent mechanism leading to apoptosis of adult cardiomyocytes. More importantly, we demonstrate that hyperosmotic stress-triggered ERS contributes to hyperglycemia-induced cell death.
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Affiliation(s)
- Juan Ignacio Burgos
- Centro de Investigaciones Cardiovasculares, CONICET La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 60 y 120, 1900, La Plata, Argentina
| | - Malena Morell
- Centro de Investigaciones Cardiovasculares, CONICET La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 60 y 120, 1900, La Plata, Argentina
| | - Juan Ignacio E Mariángelo
- Centro de Investigaciones Cardiovasculares, CONICET La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 60 y 120, 1900, La Plata, Argentina
| | - Martin Vila Petroff
- Centro de Investigaciones Cardiovasculares, CONICET La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 60 y 120, 1900, La Plata, Argentina.
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38
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Diazoxide blocks or reduces microgliosis when applied prior or subsequent to motor neuron injury in mice. Brain Res 2020; 1741:146875. [PMID: 32389588 DOI: 10.1016/j.brainres.2020.146875] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 04/23/2020] [Accepted: 05/04/2020] [Indexed: 12/11/2022]
Abstract
Diazoxide (DZX), an anti-hypertonic and anti-hypoglycemic drug, was shown to have anti-inflammatory effects in several injured cell types outside the central nervous system. In the brain, the neuroprotective potential of DZX is well described, however, its anticipated anti-inflammatory effect after acute injury has not been systematically analyzed. To disclose the anti-inflammatory effect of DZX in the central nervous system, an injury was induced in the hypoglossal and facial nuclei and in the oculomotor nucleus by unilateral axonal transection and unilateral target deprivation (enucleation), respectively. On the fourth day after surgery, microglial analysis was performed on tissue in which microglia were DAB-labeled and motoneurons were labeled with immunofluorescence. DZX treatment was given either prophylactically, starting 7 days prior to the injury and continuing until the animals were sacrificed, or postoperatively only, with daily intraperitoneal injections (1.25 mg/kg; in 10 mg/ml dimethyl sulfoxide in distilled water). Prophylactically + postoperatively applied DZX completely eliminated the microglial reaction in each motor nuclei. If DZX was applied only postoperatively, some microglial activation could be detected, but its magnitude was still significantly smaller than the non-DZX-treated controls. The effect of DZX could also be demonstrated through an extended period, as tested in the hypoglossal nucleus on day 7 after the operation. Neuronal counts, determined at day 4 after the operation in the hypoglossal nucleus, demonstrated no loss of motor neurons, however, an increased Feret's diameter of mitochondria could be measured, suggesting increased oxidative stress in the injured cells. The increase of mitochondrial Feret's diameter could also be prevented with DZX treatment.
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Federico M, Valverde CA, Mattiazzi A, Palomeque J. Unbalance Between Sarcoplasmic Reticulum Ca 2 + Uptake and Release: A First Step Toward Ca 2 + Triggered Arrhythmias and Cardiac Damage. Front Physiol 2020; 10:1630. [PMID: 32038301 PMCID: PMC6989610 DOI: 10.3389/fphys.2019.01630] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 12/24/2019] [Indexed: 12/19/2022] Open
Abstract
The present review focusses on the regulation and interplay of cardiac SR Ca2+ handling proteins involved in SR Ca2+ uptake and release, i.e., SERCa2/PLN and RyR2. Both RyR2 and SERCA2a/PLN are highly regulated by post-translational modifications and/or different partners' proteins. These control mechanisms guarantee a precise equilibrium between SR Ca2+ reuptake and release. The review then discusses how disruption of this balance alters SR Ca2+ handling and may constitute a first step toward cardiac damage and malignant arrhythmias. In the last part of the review, this concept is exemplified in different cardiac diseases, like prediabetic and diabetic cardiomyopathy, digitalis intoxication and ischemia-reperfusion injury.
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Affiliation(s)
- Marilén Federico
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E. Cingolani", CCT-La Plata/CONICET, Facultad de Cs. Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Carlos A Valverde
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E. Cingolani", CCT-La Plata/CONICET, Facultad de Cs. Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Alicia Mattiazzi
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E. Cingolani", CCT-La Plata/CONICET, Facultad de Cs. Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Julieta Palomeque
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E. Cingolani", CCT-La Plata/CONICET, Facultad de Cs. Médicas, Universidad Nacional de La Plata, La Plata, Argentina.,Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Buenos Aires, Argentina
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40
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El Refaey M, Musa H, Murphy NP, Lubbers ER, Skaf M, Han M, Cavus O, Koenig SN, Wallace MJ, Gratz D, Bradley E, Alsina KM, Wehrens XHT, Hund TJ, Mohler PJ. Protein Phosphatase 2A Regulates Cardiac Na + Channels. Circ Res 2019; 124:737-746. [PMID: 30602331 DOI: 10.1161/circresaha.118.314350] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
RATIONALE Voltage-gated Na+ channel ( INa) function is critical for normal cardiac excitability. However, the Na+ channel late component ( INa,L) is directly associated with potentially fatal forms of congenital and acquired human arrhythmia. CaMKII (Ca2+/calmodulin-dependent kinase II) enhances INa,L in response to increased adrenergic tone. However, the pathways that negatively regulate the CaMKII/Nav1.5 axis are unknown and essential for the design of new therapies to regulate the pathogenic INa,L. OBJECTIVE To define phosphatase pathways that regulate INa,L in vivo. METHODS AND RESULTS A mouse model lacking a key regulatory subunit (B56α) of the PP (protein phosphatase) 2A holoenzyme displayed aberrant action potentials after adrenergic stimulation. Unbiased computational modeling of B56α KO (knockout) mouse myocyte action potentials revealed an unexpected role of PP2A in INa,L regulation that was confirmed by direct INa,L recordings from B56α KO myocytes. Further, B56α KO myocytes display decreased sensitivity to isoproterenol-induced induction of arrhythmogenic INa,L, and reduced CaMKII-dependent phosphorylation of Nav1.5. At the molecular level, PP2A/B56α complex was found to localize and coimmunoprecipitate with the primary cardiac Nav channel, Nav1.5. CONCLUSIONS PP2A regulates Nav1.5 activity in mouse cardiomyocytes. This regulation is critical for pathogenic Nav1.5 late current and requires PP2A-B56α. Our study supports B56α as a novel target for the treatment of arrhythmia.
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Affiliation(s)
- Mona El Refaey
- From the Ohio State University College of Medicine and Wexner Medical Center, The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., D.G., E.B., T.J.H., P.J.M.).,Department of Physiology and Cell Biology, Ohio State University, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., P.J.M.)
| | - Hassan Musa
- From the Ohio State University College of Medicine and Wexner Medical Center, The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., D.G., E.B., T.J.H., P.J.M.).,Department of Physiology and Cell Biology, Ohio State University, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., P.J.M.)
| | - Nathaniel P Murphy
- From the Ohio State University College of Medicine and Wexner Medical Center, The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., D.G., E.B., T.J.H., P.J.M.).,Department of Physiology and Cell Biology, Ohio State University, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., P.J.M.)
| | - Ellen R Lubbers
- From the Ohio State University College of Medicine and Wexner Medical Center, The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., D.G., E.B., T.J.H., P.J.M.).,Department of Physiology and Cell Biology, Ohio State University, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., P.J.M.)
| | - Michel Skaf
- From the Ohio State University College of Medicine and Wexner Medical Center, The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., D.G., E.B., T.J.H., P.J.M.).,Department of Physiology and Cell Biology, Ohio State University, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., P.J.M.)
| | - Mei Han
- From the Ohio State University College of Medicine and Wexner Medical Center, The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., D.G., E.B., T.J.H., P.J.M.).,Department of Physiology and Cell Biology, Ohio State University, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., P.J.M.)
| | - Omer Cavus
- From the Ohio State University College of Medicine and Wexner Medical Center, The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., D.G., E.B., T.J.H., P.J.M.).,Department of Physiology and Cell Biology, Ohio State University, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., P.J.M.)
| | - Sara N Koenig
- From the Ohio State University College of Medicine and Wexner Medical Center, The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., D.G., E.B., T.J.H., P.J.M.).,Department of Physiology and Cell Biology, Ohio State University, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., P.J.M.)
| | - Michael J Wallace
- From the Ohio State University College of Medicine and Wexner Medical Center, The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., D.G., E.B., T.J.H., P.J.M.).,Department of Physiology and Cell Biology, Ohio State University, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., P.J.M.)
| | - Daniel Gratz
- From the Ohio State University College of Medicine and Wexner Medical Center, The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., D.G., E.B., T.J.H., P.J.M.).,Department of Biomedical Engineering, Ohio State University College of Engineering, Columbus (D.G., T.J.H.)
| | - Elisa Bradley
- From the Ohio State University College of Medicine and Wexner Medical Center, The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., D.G., E.B., T.J.H., P.J.M.).,Department of Internal Medicine, Ohio State University College of Medicine, Columbus (E.B., T.J.H., P.J.M.)
| | - Katherina M Alsina
- Department of Molecular Physiology and Biophysics (K.M.A.), Baylor College of Medicine, Houston, TX.,Division of Cardiology, Department of Medicine (K.M.A.), Baylor College of Medicine, Houston, TX.,Division of Cardiology, Department of Pediatrics (K.M.A.), Baylor College of Medicine, Houston, TX
| | - Xander H T Wehrens
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (X.H.T.W.)
| | - Thomas J Hund
- From the Ohio State University College of Medicine and Wexner Medical Center, The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., D.G., E.B., T.J.H., P.J.M.).,Department of Internal Medicine, Ohio State University College of Medicine, Columbus (E.B., T.J.H., P.J.M.).,Department of Biomedical Engineering, Ohio State University College of Engineering, Columbus (D.G., T.J.H.)
| | - Peter J Mohler
- From the Ohio State University College of Medicine and Wexner Medical Center, The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., D.G., E.B., T.J.H., P.J.M.).,Department of Internal Medicine, Ohio State University College of Medicine, Columbus (E.B., T.J.H., P.J.M.).,Department of Physiology and Cell Biology, Ohio State University, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., P.J.M.)
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Jaquenod De Giusti C, Blanco PG, Lamas PA, Carrizo Velasquez F, Lofeudo JM, Portiansky EL, Alvarez BV. Carbonic anhydrase II/sodium-proton exchanger 1 metabolon complex in cardiomyopathy of ob -/- type 2 diabetic mice. J Mol Cell Cardiol 2019; 136:53-63. [PMID: 31518570 DOI: 10.1016/j.yjmcc.2019.09.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 07/17/2019] [Indexed: 10/26/2022]
Abstract
Heart failure is the leading cause of death among diabetic people. Cellular and molecular entities leading to diabetic cardiomyopathy are, however, poorly understood. Coupling of cardiac carbonic anhydrase II (CAII) and Na+/H+ exchanger 1 (NHE1) to form a transport metabolon was analyzed in obese type 2 diabetic mice (ob-/-) and control heterozygous littermates (ob+/-). Echocardiography showed elevated systolic interventricular septum thickness and systolic posterior wall thickness in ob-/- mice at 9 and 16 weeks. ob-/- mice showed increased left ventricular (LV) weight/tibia length ratio and increased cardiomyocyte cross sectional area as compared to controls, indicating cardiac hypertrophy. Immunoblot analysis showed increased CAII expression in LV samples of ob-/-vs. ob+/- mice, and augmented Ser703 phosphorylation on NHE1 in ob-/- hearts. Reciprocal co-immunoprecipitation analysis showed strong association of CAII and NHE1 in LV samples of ob-/- mice. NHE1-dependent rate of intracellular pH (pHi) normalization after transient acid loading of isolated cardiomyocytes was higher in ob-/- mice vs. ob+/-. NHE transport activity was also augmented in cultured H9C2 rat cardiomyoblasts treated with high glucose/high palmitate, and it was normalized after CA inhibition. We conclude that the NHE1/CAII metabolon complex is exacerbated in diabetic cardiomyopathy of ob-/- mice, which may lead to perturbation of pHi and [Na+] and [Ca2+] handling in these diseased hearts.
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Affiliation(s)
- Carolina Jaquenod De Giusti
- Centro de Investigaciones Cardiovasculares CIC-CONICET, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Calle 60 y 120, 1900 La Plata, Argentina; Established Investigators of CONICET, Argentina
| | - Paula G Blanco
- Servicio de Cardiología, Facultad de Ciencias Veterinarias, UNLP, Argentina; Established Investigators of CONICET, Argentina
| | - Paula A Lamas
- Centro de Investigaciones Cardiovasculares CIC-CONICET, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Calle 60 y 120, 1900 La Plata, Argentina
| | - Fernanda Carrizo Velasquez
- Centro de Investigaciones Cardiovasculares CIC-CONICET, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Calle 60 y 120, 1900 La Plata, Argentina
| | - Juan M Lofeudo
- Centro de Investigaciones Cardiovasculares CIC-CONICET, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Calle 60 y 120, 1900 La Plata, Argentina
| | - Enrique L Portiansky
- Laboratorio de Análisis de Imágenes, Facultad de Ciencias Veterinarias, UNLP, Argentina; Established Investigators of CONICET, Argentina
| | - Bernardo V Alvarez
- Centro de Investigaciones Cardiovasculares CIC-CONICET, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Calle 60 y 120, 1900 La Plata, Argentina; Established Investigators of CONICET, Argentina.
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Tian CJ, Zhen Z. Reactive Carbonyl Species: Diabetic Complication in the Heart and Lungs. Trends Endocrinol Metab 2019; 30:546-556. [PMID: 31253519 DOI: 10.1016/j.tem.2019.05.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 05/26/2019] [Accepted: 05/28/2019] [Indexed: 12/28/2022]
Abstract
Abnormal chemical reactions in hyperglycemia alter normal metabolic processes in diabetes, which is a key process in the production of reactive carbonyls species (RCS). Increasing the concentration of RCS may result in carbonyl/oxidative stress in both the diabetic heart and lung. Ryanodine receptors (RyRs) not only play a key role in heart contraction, including rhythmic contraction and relaxation of the heart, but they are also important for controlling the airway smooth muscle. RCS modifies RyRs, resulting in RyRs dysfunction, which is involved in important mechanisms in diabetic complications. Very little is known about the mechanistic relationship between the heart and lung in diabetes. This review highlights new findings on the pathophysiological mechanisms and discusses potential approaches to treatment for these complications.
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Affiliation(s)
- Cheng-Ju Tian
- College of Rehabilitation and Sports Medicine, Jinzhou Medical University, Jinzhou, Liaoning, 121001, China.
| | - Zhong Zhen
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
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43
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Wang P, Wang SC, Yang H, Lv C, Jia S, Liu X, Wang X, Meng D, Qin D, Zhu H, Wang YF. Therapeutic Potential of Oxytocin in Atherosclerotic Cardiovascular Disease: Mechanisms and Signaling Pathways. Front Neurosci 2019; 13:454. [PMID: 31178679 PMCID: PMC6537480 DOI: 10.3389/fnins.2019.00454] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 04/23/2019] [Indexed: 12/12/2022] Open
Abstract
Coronary artery disease (CAD) is a major cardiovascular disease responsible for high morbidity and mortality worldwide. The major pathophysiological basis of CAD is atherosclerosis in association with varieties of immunometabolic disorders that can suppress oxytocin (OT) receptor (OTR) signaling in the cardiovascular system (CVS). By contrast, OT not only maintains cardiovascular integrity but also has the potential to suppress and even reverse atherosclerotic alterations and CAD. These protective effects of OT are associated with its protection of the heart and blood vessels from immunometabolic injuries and the resultant inflammation and apoptosis through both peripheral and central approaches. As a result, OT can decelerate the progression of atherosclerosis and facilitate the recovery of CVS from these injuries. At the cellular level, the protective effect of OT on CVS involves a broad array of OTR signaling events. These signals mainly belong to the reperfusion injury salvage kinase pathway that is composed of phosphatidylinositol 3-kinase-Akt-endothelial nitric oxide synthase cascades and extracellular signal-regulated protein kinase 1/2. Additionally, AMP-activated protein kinase, Ca2+/calmodulin-dependent protein kinase signaling and many others are also implicated in OTR signaling in the CVS protection. These signaling events interact coordinately at many levels to suppress the production of inflammatory cytokines and the activation of apoptotic pathways. A particular target of these signaling events is endoplasmic reticulum (ER) stress and mitochondrial oxidative stress that interact through mitochondria-associated ER membrane. In contrast to these protective effects and machineries, rare but serious cardiovascular disturbances were also reported in labor induction and animal studies including hypotension, reflexive tachycardia, coronary spasm or thrombosis and allergy. Here, we review our current understanding of the protective effect of OT against varieties of atherosclerotic etiologies as well as the approaches and underlying mechanisms of these effects. Moreover, potential cardiovascular disturbances following OT application are also discussed to avoid unwanted effects in clinical trials of OT usages.
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Affiliation(s)
- Ping Wang
- Department of Genetics, School of Basic Medical Sciences, Harbin Medical University, Harbin, China
| | - Stephani C Wang
- Department of Medicine, Albany Medical Center, Albany, NY, United States
| | - Haipeng Yang
- Department of Pediatrics, The Forth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Chunmei Lv
- Department of Physiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, China
| | - Shuwei Jia
- Department of Physiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, China
| | - Xiaoyu Liu
- Department of Physiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, China
| | - Xiaoran Wang
- Department of Physiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, China
| | - Dexin Meng
- Department of Physiology, Jiamusi University, Jiamusi, China
| | - Danian Qin
- Department of Physiology, Shantou University of Medical College, Shantou, China
| | - Hui Zhu
- Department of Physiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, China
| | - Yu-Feng Wang
- Department of Physiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, China
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Dai W, Laforest B, Tyan L, Shen KM, Nadadur RD, Alvarado FJ, Mazurek SR, Lazarevic S, Gadek M, Wang Y, Li Y, Valdivia HH, Shen L, Broman MT, Moskowitz IP, Weber CR. A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice. eLife 2019; 8:41814. [PMID: 30896405 PMCID: PMC6428569 DOI: 10.7554/elife.41814] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 02/28/2019] [Indexed: 02/06/2023] Open
Abstract
Risk for Atrial Fibrillation (AF), the most common human arrhythmia, has a major genetic component. The T-box transcription factor TBX5 influences human AF risk, and adult-specific Tbx5-mutant mice demonstrate spontaneous AF. We report that TBX5 is critical for cellular Ca2+ homeostasis, providing a molecular mechanism underlying the genetic implication of TBX5 in AF. We show that cardiomyocyte action potential (AP) abnormalities in Tbx5-deficient atrial cardiomyocytes are caused by a decreased sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2)-mediated SR calcium uptake which was balanced by enhanced trans-sarcolemmal calcium fluxes (calcium current and sodium/calcium exchanger), providing mechanisms for triggered activity. The AP defects, cardiomyocyte ectopy, and AF caused by TBX5 deficiency were rescued by phospholamban removal, which normalized SERCA function. These results directly link transcriptional control of SERCA2 activity, depressed SR Ca2+ sequestration, enhanced trans-sarcolemmal calcium fluxes, and AF, establishing a mechanism underlying the genetic basis for a Ca2+-dependent pathway for AF risk. The human heart contains four distinct chambers that work together to pump blood around the body. In individuals with a condition called atrial fibrillation, two of the chambers (known as the atria) beat irregularly and are unable to push all the blood they hold into the other two chambers of the heart. This can cause heart failure and increases the likelihood of blood clots, which may lead to stroke and heart attacks. Small molecules called calcium ions play a crucial role in regulating how and when the atria contract by driving electrical activity in heart cells. To contract the atria, a storage compartment within heart cells known as the sarcoplasmic reticulum releases calcium ions into the main compartment of the cells. Calcium ions also enter the cell from the surrounding tissue. As the atria relax, calcium ions are pumped back into the sarcoplasmic reticulum or out of the cell by specific transport proteins. Individuals with mutations in a gene called Tbx5 are more likely to develop atrial fibrillation than other people, but it was not clear how such gene mutations contribute to the disease. Here, Dai, Laforest et al. used mice with a mutation in the Tbx5 gene to study how defects in Tbx5 affect electrical activity in heart cells. The experiments found that the Tbx5 gene was critical for calcium ions to drive normal electrical activity in mouse heart cells. Compared with heart cells from normal mice, the heart cells from the mutant mice had decreased flow of calcium ions into the sarcoplasmic reticulum and increased flow of calcium ions out of the cell. These findings provide a direct link between atrial fibrillation and the flow of calcium ions in heart cells. Together with previous work, these findings indicate that multiple different mechanisms could lead to atrial fibrillation, but that many of these involve changes in the flow of calcium ions. Therefore, personalized medicine, where clinicians uncover the specific mechanisms responsible for atrial fibrillation in individual patients, may play an important role in treating this condition in the future.
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Affiliation(s)
- Wenli Dai
- Department of Pathology, University of Chicago, Chicago, United States
| | - Brigitte Laforest
- Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, United States
| | - Leonid Tyan
- Department of Pathology, University of Chicago, Chicago, United States
| | - Kaitlyn M Shen
- Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, United States
| | - Rangarajan D Nadadur
- Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, United States
| | - Francisco J Alvarado
- Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, United States
| | - Stefan R Mazurek
- Department of Medicine, University of Chicago, Chicago, United States
| | - Sonja Lazarevic
- Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, United States
| | - Margaret Gadek
- Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, United States
| | - Yitang Wang
- Department of Pathology, University of Chicago, Chicago, United States
| | - Ye Li
- Department of Pathology, University of Chicago, Chicago, United States
| | - Hector H Valdivia
- Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, United States
| | - Le Shen
- Department of Pathology, University of Chicago, Chicago, United States.,Section of Neurosurgery, Department of Surgery, University of Chicago, Chicago, United States
| | - Michael T Broman
- Department of Medicine, University of Chicago, Chicago, United States
| | - Ivan P Moskowitz
- Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, United States
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Alvarado FJ, Bos JM, Yuchi Z, Valdivia CR, Hernández JJ, Zhao YT, Henderlong DS, Chen Y, Booher TR, Marcou CA, Van Petegem F, Ackerman MJ, Valdivia HH. Cardiac hypertrophy and arrhythmia in mice induced by a mutation in ryanodine receptor 2. JCI Insight 2019; 5:126544. [PMID: 30835254 DOI: 10.1172/jci.insight.126544] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Hypertrophic cardiomyopathy (HCM) is triggered mainly by mutations in genes encoding sarcomeric proteins, but a significant proportion of patients lack a genetic diagnosis. We identified a novel mutation in the ryanodine receptor 2, RyR2-P1124L, in a patient from a genotype-negative HCM cohort. The aim of this study was to determine whether RyR2-P1124L triggers functional and structural alterations in isolated RyR2 channels and whole hearts. We found that P1124L induces significant conformational changes in the SPRY2 domain of RyR2. Recombinant RyR2-P1124L channels displayed a cytosolic loss-of-function phenotype, which contrasted with a higher sensitivity to luminal [Ca2+], indicating a luminal gain-of-function. Homozygous mice for RyR2-P1124L showed mild cardiac hypertrophy, similar to the human patient. This phenotype, evident at 1 yr of age, was accompanied by an increase in the expression of calmodulin (CaM). P1124L mice also showed higher susceptibility to arrhythmia at 8 mo of age, before the onset of hypertrophy. RyR2-P1124L has a distinct cytosolic loss-of-function and a luminal gain-of-function phenotype. This bifunctionally-divergent behavior triggers arrhythmias and structural cardiac remodeling, and involves overexpression of calmodulin as a potential hypertrophic mediator. This study is relevant to continue elucidating the possible causes of genotype-negative HCM and the role of RyR2 in cardiac hypertrophy.
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Affiliation(s)
- Francisco J Alvarado
- Department of Medicine, Division of Cardiovascular Medicine, and Cardiovascular Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA
| | - J Martijn Bos
- Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, and.,Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomic Laboratory, Mayo Clinic, Rochester, Minnesota, USA
| | - Zhiguang Yuchi
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Carmen R Valdivia
- Department of Medicine, Division of Cardiovascular Medicine, and Cardiovascular Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Jonathan J Hernández
- Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA
| | | | - Dawn S Henderlong
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Yan Chen
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Talia R Booher
- Department of Medicine, Division of Cardiovascular Medicine, and Cardiovascular Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Cherisse A Marcou
- Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomic Laboratory, Mayo Clinic, Rochester, Minnesota, USA
| | - Filip Van Petegem
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Michael J Ackerman
- Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, and.,Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomic Laboratory, Mayo Clinic, Rochester, Minnesota, USA.,Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Mayo Clinic, Rochester, Minnesota, USA
| | - Héctor H Valdivia
- Department of Medicine, Division of Cardiovascular Medicine, and Cardiovascular Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA
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Hegyi B, Bers DM, Bossuyt J. CaMKII signaling in heart diseases: Emerging role in diabetic cardiomyopathy. J Mol Cell Cardiol 2019; 127:246-259. [PMID: 30633874 DOI: 10.1016/j.yjmcc.2019.01.001] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 01/04/2019] [Indexed: 02/07/2023]
Abstract
Calcium/calmodulin-dependent protein kinase II (CaMKII) is upregulated in diabetes and significantly contributes to cardiac remodeling with increased risk of cardiac arrhythmias. Diabetes is frequently associated with atrial fibrillation, coronary artery disease, and heart failure, which may further enhance CaMKII. Activation of CaMKII occurs downstream of neurohormonal stimulation (e.g. via G-protein coupled receptors) and involve various posttranslational modifications including autophosphorylation, oxidation, S-nitrosylation and O-GlcNAcylation. CaMKII signaling regulates diverse cellular processes in a spatiotemporal manner including excitation-contraction and excitation-transcription coupling, mechanics and energetics in cardiac myocytes. Chronic activation of CaMKII results in cellular remodeling and ultimately arrhythmogenic alterations in Ca2+ handling, ion channels, cell-to-cell coupling and metabolism. This review addresses the detrimental effects of the upregulated CaMKII signaling to enhance the arrhythmogenic substrate and trigger mechanisms in the heart. We also briefly summarize preclinical studies using kinase inhibitors and genetically modified mice targeting CaMKII in diabetes. The mechanistic understanding of CaMKII signaling, cardiac remodeling and arrhythmia mechanisms may reveal new therapeutic targets and ultimately better treatment in diabetes and heart disease in general.
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Affiliation(s)
- Bence Hegyi
- Department of Pharmacology, University of California Davis, Davis, CA, USA
| | - Donald M Bers
- Department of Pharmacology, University of California Davis, Davis, CA, USA.
| | - Julie Bossuyt
- Department of Pharmacology, University of California Davis, Davis, CA, USA
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47
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Boskovic M, Bundalo M, Zivkovic M, Stanisic J, Kostic M, Koricanac G, Stankovic A. Estradiol ameliorates antioxidant axis SIRT1-FoxO3a-MnSOD/catalase in the heart of fructose-fed ovariectomized rats. J Funct Foods 2019. [DOI: 10.1016/j.jff.2018.11.053] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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Grain Amaranth Is Associated with Improved Hepatic and Renal Calcium Metabolism in Type 2 Diabetes Mellitus of Male Wistar Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:4098942. [PMID: 30420893 PMCID: PMC6211157 DOI: 10.1155/2018/4098942] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 09/20/2018] [Accepted: 10/02/2018] [Indexed: 12/14/2022]
Abstract
Background Dysregulation of calcium signaling is a hallmark of diabetes mellitus (DM) and grain amaranth (AG) has antidiabetic properties. Information on the mechanism of action of AG on blood, renal, and hepatic tissues is sparse, although it continues to be an important alternative medicinal plant in several developing countries. The objective of the study was to determine key changes in calcium levels and s100a1 protein levels and antioxidant and histopathologic changes in blood, renal, and hepatic tissues of male diabetic Wistar rats. Materials and Methods This was an experimental study in which 30 male Wistar rats were kept for 5 weeks (6 groups, N =5). Groups 1-IV had T2DM induced using Nicotinamide and Streptozotocin: Group I, Mixtard®; group II, positive control; group III, 25% AG; group IV, 50% AG. Furthermore, group V consisted of normal rats given 50% GA and group VI was negative control. Blood, renal, and hepatic tissues were collected and analyzed for calcium, s100a1 protein levels, and antioxidant and histopathological changes. Results and Discussion In blood, renal, and hepatic tissue, calcium and s100a1 levels were low during T2DM and these increased following AG supplementation. This was important for improved metabolic processes, thus leading to the low malondialdehyde (MDA) and glutathione peroxidase (GPx) activity in the tissues. Efficient antioxidant status was important for improved calcium signaling mechanisms, thus leading to improved tissue function and protection demonstrating the importance of AG as an alternative medicinal source through the calcium signaling pathway. Conclusion Grain amaranth exerts its antidiabetic properties through improved calcium homeostasis in blood, kidney, and liver.
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Wang Y, Zhao R, Liu D, Deng W, Xu G, Liu W, Rong J, Long X, Ge J, Shi B. Exosomes Derived from miR-214-Enriched Bone Marrow-Derived Mesenchymal Stem Cells Regulate Oxidative Damage in Cardiac Stem Cells by Targeting CaMKII. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:4971261. [PMID: 30159114 PMCID: PMC6109555 DOI: 10.1155/2018/4971261] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Revised: 04/24/2018] [Accepted: 05/17/2018] [Indexed: 12/23/2022]
Abstract
Cardiac stem cells (CSCs) have emerged as one of the most promising stem cells for cardiac protection. Recently, exosomes from bone marrow-derived mesenchymal stem cells (BMSCs) have been found to facilitate cell proliferation and survival by transporting various bioactive molecules, including microRNAs (miRs). In this study, we found that BMSC-derived exosomes (BMSC-exos) significantly decreased apoptosis rates and reactive oxygen species (ROS) production in CSCs after oxidative stress injury. Moreover, a stronger effect was induced by exosomes collected from BMSCs cultured under hypoxic conditions (Hypoxic-exos) than those collected from BMSCs cultured under normal conditions (Nor-exos). We also observed greater miR-214 enrichment in Hypoxic-exos than in Nor-exos. In addition, a miR-214 inhibitor or mimics added to modulate miR-214 levels in BMSC-exos revealed that exosomes from miR-214-depleted BMSCs partially reversed the effects of hypoxia-induced exosomes on oxidative damage in CSCs. These data further confirmed that miR-214 is the main effector molecule in BMSC-exos that protects CSCs from oxidative damage. miR-214 mimic and inhibitor transfection assays verified that CaMKII is a target gene of miR-214 in CSCs, with exosome-pretreated CSCs exhibiting increased miR-214 levels but decreased CaMKII levels. Therefore, the miR-214/CaMKII axis regulates oxidative stress-related injury in CSCs, such as apoptosis, calcium homeostasis disequilibrium, and excessive ROS accumulation. Collectively, these findings suggest that BMSCs release miR-214-containing exosomes to suppress oxidative stress injury in CSCs through CaMKII silencing.
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Affiliation(s)
- Yan Wang
- Department of Cardiology, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, China
| | - Ranzun Zhao
- Department of Cardiology, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, China
| | - Debin Liu
- Department of Cardiology, Shantou Glory Hospital, Shantou 515041, China
| | - Wenwen Deng
- Department of Cardiology, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, China
| | - Guanxue Xu
- Department of Cardiology, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, China
| | - Weiwei Liu
- Department of Cardiology, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, China
| | - Jidong Rong
- Department of Cardiology, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, China
| | - Xianping Long
- Department of Cardiology, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, China
| | - Junbo Ge
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Bei Shi
- Department of Cardiology, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, China
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Beckendorf J, van den Hoogenhof MMG, Backs J. Physiological and unappreciated roles of CaMKII in the heart. Basic Res Cardiol 2018; 113:29. [PMID: 29905892 PMCID: PMC6003982 DOI: 10.1007/s00395-018-0688-8] [Citation(s) in RCA: 122] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 06/11/2018] [Indexed: 12/27/2022]
Abstract
In the cardiomyocyte, CaMKII has been identified as a nodal influencer of excitation-contraction and also excitation-transcription coupling. Its activity can be regulated in response to changes in intracellular calcium content as well as after several post-translational modifications. Some of the effects mediated by CaMKII may be considered adaptive, while effects of sustained CaMKII activity may turn into the opposite and are detrimental to cardiac integrity and function. As such, CaMKII has long been noted as a promising target for pharmacological inhibition, but the ubiquitous nature of CaMKII has made it difficult to target CaMKII specifically where it is detrimental. In this review, we provide a brief overview of the physiological and pathophysiological properties of CaMKII signaling, but we focus on the physiological and adaptive functions of CaMKII. Furthermore, special consideration is given to the emerging role of CaMKII as a mediator of inflammatory processes in the heart.
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Affiliation(s)
- Jan Beckendorf
- Department for Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany.,Department for Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Maarten M G van den Hoogenhof
- Department for Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Johannes Backs
- Department for Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany. .,DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
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