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Ji YW, Wen XY, Tang HP, Su WT, Xia ZY, Lei SQ. Necroptosis: a significant and promising target for intervention of cardiovascular disease. Biochem Pharmacol 2025; 237:116951. [PMID: 40268251 DOI: 10.1016/j.bcp.2025.116951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 03/18/2025] [Accepted: 04/14/2025] [Indexed: 04/25/2025]
Abstract
Due to changes in dietary structures, population aging, and the exacerbation of metabolic risk factors, the incidence of cardiovascular disease continues to rise annually, posing a significant health burden worldwide. Cell death plays a crucial role in the onset and progression of cardiovascular diseases. As a regulated endpoint encountered by cells under adverse stress conditions, the execution of necroptosis is regulated by classicalpathways, the calmodulin-dependent protein kinases (CaMK) pathway, and mitochondria-dependent pathways, and implicated in various cardiovascular diseases, including atherosclerosis, myocardial infarction, myocardial ischemia-reperfusion injury (IRI), heart failure, diabetic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, chemotherapy drug-induced cardiomyopathy, and abdominal aortic aneurysm (AAA). To further investigate potential therapeutic targets for cardiovascular diseases, we also analyzed the main molecules and their inhibitors involved in necroptosis in an effort to uncover insights for treatment.
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Affiliation(s)
- Yan-Wei Ji
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xin-Yu Wen
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - He-Peng Tang
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wa-Ting Su
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhong-Yuan Xia
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shao-Qing Lei
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
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2
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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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3
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Qie B, Tuo J, Chen F, Ding H, Lyu L. Gene therapy for genetic diseases: challenges and future directions. MedComm (Beijing) 2025; 6:e70091. [PMID: 39949979 PMCID: PMC11822459 DOI: 10.1002/mco2.70091] [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: 08/16/2024] [Revised: 01/08/2025] [Accepted: 01/09/2025] [Indexed: 02/16/2025] Open
Abstract
Genetic diseases constitute the majority of rare human diseases, resulting from abnormalities in an individual's genetic composition. Traditional treatments offer limited relief for these challenging conditions. In contrast, the rapid advancement of gene therapy presents significant advantages by directly addressing the underlying causes of genetic diseases, thereby providing the potential for precision treatment and the possibility of curing these disorders. This review aims to delineate the mechanisms and outcomes of current gene therapy approaches in clinical applications across various genetic diseases affecting different body systems. Additionally, genetic muscular disorders will be examined as a case study to investigate innovative strategies of novel therapeutic approaches, including gene replacement, gene suppression, gene supplementation, and gene editing, along with their associated advantages and limitations at both clinical and preclinical levels. Finally, this review emphasizes the existing challenges of gene therapy, such as vector packaging limitations, immunotoxicity, therapy specificity, and the subcellular localization and immunogenicity of therapeutic cargos, while discussing potential optimization directions for future research. Achieving delivery specificity, as well as long-term effectiveness and safety, will be crucial for the future development of gene therapies targeting genetic diseases.
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Affiliation(s)
- Beibei Qie
- Institute of Sports Medicine and Health, School of Sports Medicine and HealthChengdu Sport UniversityChengduChina
| | - Jianghua Tuo
- Institute of Sports Medicine and Health, School of Sports Medicine and HealthChengdu Sport UniversityChengduChina
| | - Feilong Chen
- Institute of Sports Medicine and Health, School of Sports Medicine and HealthChengdu Sport UniversityChengduChina
| | - Haili Ding
- Institute of Sports Medicine and Health, School of Sports Medicine and HealthChengdu Sport UniversityChengduChina
| | - Lei Lyu
- Institute of Sports Medicine and Health, School of Sports Medicine and HealthChengdu Sport UniversityChengduChina
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Li JP, Qiu S, Tai GJ, Liu YM, Wei W, Fu MM, Fang PQ, Otieno JN, Battulga T, Li XX, Xu M. NLRP3 inflammasome-modulated angiogenic function of EPC via PI3K/ Akt/mTOR pathway in diabetic myocardial infarction. Cardiovasc Diabetol 2025; 24:6. [PMID: 39762890 PMCID: PMC11705910 DOI: 10.1186/s12933-024-02541-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Inflammatory diseases impair the reparative properties of endothelial progenitor cells (EPC); however, the involvement of diabetes in EPC dysfunction associated with myocardial infarction (MI) remains unknown. METHODS A model was established combining high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice with myocardial infarction. The therapeutic effects of transplanted wild-type EPC, Nlrp3 knockout EPC, and Nlrp3 overexpression EPC were evaluated. Chip and Luciferase assay revealed CEBPB regulated the transcriptional expression of Nlrp3 as a transcription factor in EPC stimulated by high glucose (HG) or advanced glycation end products (AGEs). CO-IP results suggested that USP14 selectively suppressed NLRP3 degradation. KEGG enrichment revealed PI3K/ Akt/mTOR signaling showed striking significance in the entire pathway. RESULTS In our study, wild-type, Nlrp3 knockout and Nlrp3 overexpressed EPC, intracardiac injections effectively improved cardiac function, increased angiogenesis, and reduced infarct size in mice with myocardial infarction. However, in the HFD/STZ-induced diabetic mice model combined with myocardial infarction, Nlrp3 knockout EPC significantly restored angiogenic capacity. Mechanically, CEBPB regulated the transcriptional level of Nlrp3 as a transcription factor in EPC. Meanwhile, we found that USP14 selectively suppressed NLRP3 protein degradation through the USP motif on the NACHT domain in mediating inflammasome activation. Cardiac functional outcomes in recipient mice after intramyocardial injection of shNlrp3 EPC overexpressing CEBPB or USP14 validated the modulation of EPC function by regulating Nlrp3 transcription or post-translational modification. Furthermore, KEGG enrichment and validation at the protein levels revealed PI3K/ Akt/mTOR cascade might be a downstream signal for NLRP3 inflammasome. CONCLUSION Our study provides a new understanding of how diabetes affected progenitor cell-mediated cardiac repair and identifies NLRP3 as a new therapeutic target for improving myocardial infarction repair in inflammatory diseases.
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Affiliation(s)
- Jia-Peng Li
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tong jia Lane, Nanjing, 210009, People's Republic of China
| | - Shu Qiu
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tong jia Lane, Nanjing, 210009, People's Republic of China
| | - Guang-Jie Tai
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tong jia Lane, Nanjing, 210009, People's Republic of China
| | - Yi-Ming Liu
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210009, People's Republic of China
| | - Wei Wei
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tong jia Lane, Nanjing, 210009, People's Republic of China
| | - Meng-Meng Fu
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tong jia Lane, Nanjing, 210009, People's Republic of China
| | - Pan-Qi Fang
- Department of Pharmacy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, People's Republic of China
| | - Joseph Nicolao Otieno
- Director Institute of Traditional Medicine, Muhimbili University of Health and Allied Sciencea, P.O.BOX 65001, Dar es Salaam, Tanzania
| | - Tungalag Battulga
- School of Pharmacy, Mongolian National University of Medical Sciences, 24210, Ulaanbaatar, Mongolia
| | - Xiao-Xue Li
- Department of Cardiology, School of Medicine, Zhongda Hospital, Southeast University, 87 Ding Jiaqiao, Nanjing, 210009, People's Republic of China
| | - Ming Xu
- Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tong jia Lane, Nanjing, 210009, People's Republic of China.
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Lauerer AM, Caravia XM, Maier LS, Chemello F, Lebek S. Gene editing in common cardiovascular diseases. Pharmacol Ther 2024; 263:108720. [PMID: 39284367 DOI: 10.1016/j.pharmthera.2024.108720] [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: 05/20/2024] [Revised: 07/29/2024] [Accepted: 09/01/2024] [Indexed: 09/22/2024]
Abstract
Cardiovascular diseases are the leading cause of morbidity and mortality worldwide, highlighting the high socioeconomic impact. Current treatment strategies like compound-based drugs or surgeries are often limited. On the one hand, systemic administration of substances is frequently associated with adverse side effects; on the other hand, they typically provide only short-time effects requiring daily intake. Thus, new therapeutic approaches and concepts are urgently needed. The advent of CRISPR-Cas9 genome editing offers great promise for the correction of disease-causing hereditary mutations. As such mutations are often very rare, gene editing strategies to correct them are not broadly applicable to many patients. Notably, there is recent evidence that gene editing technology can also be deployed to disrupt common pathogenic signaling cascades in a targeted, specific, and efficient manner, which offers a more generalizable approach. However, several challenges remain to be addressed ranging from the optimization of the editing strategy itself to a suitable delivery strategy up to potential immune responses to the editing components. This review article discusses important CRISPR-Cas9-based gene editing approaches with their advantages and drawbacks and outlines opportunities in their application for treatment of cardiovascular diseases.
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Affiliation(s)
- Anna-Maria Lauerer
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Xurde M Caravia
- Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Lars S Maier
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Francesco Chemello
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Simon Lebek
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.
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6
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Lee WS, Abel ED, Kim J. New Insights into IGF-1 Signaling in the Heart. Physiology (Bethesda) 2024; 39:0. [PMID: 38713091 DOI: 10.1152/physiol.00003.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 04/24/2024] [Accepted: 05/04/2024] [Indexed: 05/08/2024] Open
Abstract
Insulin-like growth factor-1 (IGF-1) signaling has multiple physiological roles in cellular growth, metabolism, and aging. Myocardial hypertrophy, cell death, senescence, fibrosis, and electrical remodeling are hallmarks of various heart diseases and contribute to the progression of heart failure. This review highlights the critical role of IGF-1 and its cognate receptor in cardiac hypertrophy, aging, and remodeling.
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Affiliation(s)
- Wang-Soo Lee
- Division of Cardiology, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - E Dale Abel
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States
| | - Jaetaek Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
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7
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Ricci E, Mazhar F, Marzolla M, Severi S, Bartolucci C. Sinoatrial node heterogeneity and fibroblasts increase atrial driving capability in a two-dimensional human computational model. Front Physiol 2024; 15:1408626. [PMID: 39139481 PMCID: PMC11319284 DOI: 10.3389/fphys.2024.1408626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 06/04/2024] [Indexed: 08/15/2024] Open
Abstract
Background: Cardiac pacemaking remains an unsolved matter from many perspectives. Extensive experimental and computational studies have been performed to describe the sinoatrial physiology across different scales, from the molecular to clinical levels. Nevertheless, the mechanism by which a heartbeat is generated inside the sinoatrial node and propagated to the working myocardium is not fully understood at present. This work aims to provide quantitative information about this fascinating phenomenon, especially regarding the contributions of cellular heterogeneity and fibroblasts to sinoatrial node automaticity and atrial driving. Methods: We developed a bidimensional computational model of the human right atrial tissue, including the sinoatrial node. State-of-the-art knowledge of the anatomical and physiological aspects was adopted during the design of the baseline tissue model. The novelty of this study is the consideration of cellular heterogeneity and fibroblasts inside the sinoatrial node for investigating the manner by which they tune the robustness of stimulus formation and conduction under different conditions (baseline, ionic current blocks, autonomic modulation, and external high-frequency pacing). Results: The simulations show that both heterogeneity and fibroblasts significantly increase the safety factor for conduction by more than 10% in almost all the conditions tested and shorten the sinus node recovery time after overdrive suppression by up to 60%. In the human model, especially under challenging conditions, the fibroblasts help the heterogeneous myocytes to synchronise their rate (e.g. -82% inσ C L under 25 nM of acetylcholine administration) and capture the atrium (with 25% L-type calcium current block). However, the anatomical and gap junctional coupling aspects remain the most important model parameters that allow effective atrial excitations. Conclusion: Despite the limitations to the proposed model, this work suggests a quantitative explanation to the astonishing overall heterogeneity shown by the sinoatrial node.
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Affiliation(s)
- Eugenio Ricci
- Department of Electrical, Electronic, and Information Engineering “Guglielmo Marconi”, University of Bologna, Cesena, Italy
| | - Fazeelat Mazhar
- Department of Electrical, Electronic, and Information Engineering “Guglielmo Marconi”, University of Bologna, Cesena, Italy
| | - Moreno Marzolla
- Department of Computer Science and Engineering, University of Bologna, Cesena, Italy
| | - Stefano Severi
- Department of Electrical, Electronic, and Information Engineering “Guglielmo Marconi”, University of Bologna, Cesena, Italy
| | - Chiara Bartolucci
- Department of Electrical, Electronic, and Information Engineering “Guglielmo Marconi”, University of Bologna, Cesena, Italy
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Xie S, Sun Y, Zhao X, Xiao Y, Zhou F, Lin L, Wang W, Lin B, Wang Z, Fang Z, Wang L, Zhang Y. An update of the molecular mechanisms underlying anthracycline induced cardiotoxicity. Front Pharmacol 2024; 15:1406247. [PMID: 38989148 PMCID: PMC11234178 DOI: 10.3389/fphar.2024.1406247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 06/10/2024] [Indexed: 07/12/2024] Open
Abstract
Anthracycline drugs mainly include doxorubicin, epirubicin, pirarubicin, and aclamycin, which are widely used to treat a variety of malignant tumors, such as breast cancer, gastrointestinal tumors, lymphoma, etc. With the accumulation of anthracycline drugs in the body, they can induce serious heart damage, limiting their clinical application. The mechanism by which anthracycline drugs cause cardiotoxicity is not yet clear. This review provides an overview of the different types of cardiac damage induced by anthracycline-class drugs and delves into the molecular mechanisms behind these injuries. Cardiac damage primarily involves alterations in myocardial cell function and pathological cell death, encompassing mitochondrial dysfunction, topoisomerase inhibition, disruptions in iron ion metabolism, myofibril degradation, and oxidative stress. Mechanisms of uptake and transport in anthracycline-induced cardiotoxicity are emphasized, as well as the role and breakthroughs of iPSC in cardiotoxicity studies. Selected novel cardioprotective therapies and mechanisms are updated. Mechanisms and protective strategies associated with anthracycline cardiotoxicity in animal experiments are examined, and the definition of drug damage in humans and animal models is discussed. Understanding these molecular mechanisms is of paramount importance in mitigating anthracycline-induced cardiac toxicity and guiding the development of safer approaches in cancer treatment.
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Affiliation(s)
- Sicong Xie
- Department of Rehabilitation Medicine, School of Acupuncture-Moxibustion and Tuina and School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuwei Sun
- Department of Rehabilitation Medicine, School of Acupuncture-Moxibustion and Tuina and School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xuan Zhao
- Department of General Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yiqun Xiao
- Department of Rehabilitation Medicine, School of Acupuncture-Moxibustion and Tuina and School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, China
| | - Fei Zhou
- Department of Rehabilitation Medicine, School of Acupuncture-Moxibustion and Tuina and School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, China
| | - Liang Lin
- Department of Rehabilitation Medicine, School of Acupuncture-Moxibustion and Tuina and School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wei Wang
- College of Electronic and Optical Engineering and College of Flexible Electronics, Future Technology, Nanjing University of Posts and Telecommunications, Nanjing, China
| | - Bin Lin
- Key Laboratory of Intelligent Pharmacy and Individualized Therapy of Huzhou, Department of Pharmacy, Changxing People's Hospital, Huzhou, China
| | - Zun Wang
- Department of Rehabilitation Medicine, School of Acupuncture-Moxibustion and Tuina and School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zixuan Fang
- Department of Rehabilitation Medicine, School of Acupuncture-Moxibustion and Tuina and School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lei Wang
- Department of Rehabilitation Medicine, School of Acupuncture-Moxibustion and Tuina and School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yang Zhang
- Department of Rehabilitation Medicine, School of Acupuncture-Moxibustion and Tuina and School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory of Intelligent Pharmacy and Individualized Therapy of Huzhou, Department of Pharmacy, Changxing People's Hospital, Huzhou, China
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Zhou X, Liu H, Feng F, Kang GJ, Liu M, Guo Y, Dudley SC. Macrophage IL-1β mediates atrial fibrillation risk in diabetic mice. JCI Insight 2024; 9:e171102. [PMID: 38889387 PMCID: PMC11383594 DOI: 10.1172/jci.insight.171102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/14/2024] [Indexed: 06/20/2024] Open
Abstract
Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). The mechanisms underlying DM-associated AF are unclear. AF and DM are both related to inflammation. We investigated whether DM-associated inflammation contributed to AF risk. Mice were fed with high-fat diet to induce type II DM and were subjected to IL-1β antibodies, macrophage depletion by clodronate liposomes, a mitochondrial antioxidant (mitoTEMPO), or a cardiac ryanodine receptor 2 (RyR2) stabilizer (S107). All tests were performed at 36-38 weeks of age. DM mice presented with increased AF inducibility, enhanced mitochondrial reactive oxygen species (mitoROS) generation, and activated innate immunity in the atria, as evidenced by enhanced monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, and IL-1β levels. Signs of aberrant RyR2 Ca2+ leak were observed in the atria of DM mice. IL-1β neutralization, macrophage depletion, and exposure to mitoTEMPO and S107 significantly ameliorated the AF vulnerability in DM mice. Atrial overexpression of MCP-1 increased AF occurrence in normal mice through the same mechanistic signaling cascade as observed in DM mice. In conclusion, macrophage-mediated IL-1β contributed to DM-associated AF risk through mitoROS modulation of RyR2 Ca2+ leak.
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Sun Y, Hao M, Wu H, Zhang C, Wei D, Li S, Song Z, Tao Y. Unveiling the role of CaMKII in retinal degeneration: from biological mechanism to therapeutic strategies. Cell Biosci 2024; 14:59. [PMID: 38725013 PMCID: PMC11084033 DOI: 10.1186/s13578-024-01236-2] [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: 01/06/2024] [Accepted: 04/18/2024] [Indexed: 05/12/2024] Open
Abstract
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a family of broad substrate specificity serine (Ser)/threonine (Thr) protein kinases that play a crucial role in the Ca2+-dependent signaling pathways. Its significance as an intracellular Ca2+ sensor has garnered abundant research interest in the domain of neurodegeneration. Accumulating evidences suggest that CaMKII is implicated in the pathology of degenerative retinopathies such as diabetic retinopathy (DR), age-related macular degeneration (AMD), retinitis pigmentosa (RP) and glaucoma optic neuropathy. CaMKII can induce the aberrant proliferation of retinal blood vessels, influence the synaptic signaling, and exert dual effects on the survival of retinal ganglion cells and pigment epithelial cells. Researchers have put forth multiple therapeutic agents, encompassing small molecules, peptides, and nucleotides that possess the capability to modulate CaMKII activity. Due to its broad range isoforms and splice variants therapeutic strategies seek to inhibit specifically the CaMKII are confronted with considerable challenges. Therefore, it becomes crucial to discern the detrimental and advantageous aspects of CaMKII, thereby facilitating the development of efficacious treatment. In this review, we summarize recent research findings on the cellular and molecular biology of CaMKII, with special emphasis on its metabolic and regulatory mechanisms. We delve into the involvement of CaMKII in the retinal signal transduction pathways and discuss the correlation between CaMKII and calcium overload. Furthermore, we elaborate the therapeutic trials targeting CaMKII, and introduce recent developments in the zone of CaMKII inhibitors. These findings would enrich our knowledge of CaMKII, and shed light on the development of a therapeutic target for degenerative retinopathy.
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Affiliation(s)
- Yuxin Sun
- Department of Ophthalmology, Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, China
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Mengyu Hao
- Department of Ophthalmology, Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, China
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Hao Wu
- Department of Ophthalmology, Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, China
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Chengzhi Zhang
- Department of Ophthalmology, Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, China
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Dong Wei
- Department of Ophthalmology, Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, China
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Siyu Li
- Department of Ophthalmology, Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, China
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Zongming Song
- Department of Ophthalmology, Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, China.
| | - Ye Tao
- Department of Ophthalmology, Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, China.
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China.
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11
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Peyret H, Konecki C, Terryn C, Dubuisson F, Millart H, Feliu C, Djerada Z. Methylglyoxal induces cardiac dysfunction through mechanisms involving altered intracellular calcium handling in the rat heart. Chem Biol Interact 2024; 394:110949. [PMID: 38555048 DOI: 10.1016/j.cbi.2024.110949] [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: 10/21/2023] [Revised: 02/19/2024] [Accepted: 03/07/2024] [Indexed: 04/02/2024]
Abstract
Methylglyoxal (MGO) is an endogenous, highly reactive dicarbonyl metabolite generated under hyperglycaemic conditions. MGO plays a role in developing pathophysiological conditions, including diabetic cardiomyopathy. However, the mechanisms involved and the molecular targets of MGO in the heart have not been elucidated. In this work, we studied the exposure-related effects of MGO on cardiac function in an isolated perfused rat heart ex vivo model. The effect of MGO on calcium homeostasis in cardiomyocytes was studied in vitro by the fluorescence indicator of intracellular calcium Fluo-4. We demonstrated that MGO induced cardiac dysfunction, both in contractility and diastolic function. In rat heart, the effects of MGO treatment were significantly limited by aminoguanidine, a scavenger of MGO, ruthenium red, a general cation channel blocker, and verapamil, an L-type voltage-dependent calcium channel blocker, demonstrating that this dysfunction involved alteration of calcium regulation. MGO induced a significant concentration-dependent increase of intracellular calcium in neonatal rat cardiomyocytes, which was limited by aminoguanidine and verapamil. These results suggest that the functionality of various calcium channels is altered by MGO, particularly the L-type calcium channel, thus explaining its cardiac toxicity. Therefore, MGO could participate in the development of diabetic cardiomyopathy through its impact on calcium homeostasis in cardiac cells.
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Affiliation(s)
- Hélène Peyret
- Université de Reims Champagne Ardenne, UR 3801 PPF, Reims, 51100, France
| | - Céline Konecki
- Université de Reims Champagne Ardenne, UR 3801 PPF, Reims, 51100, France; Centre Hospitalier Universitaire de Reims, Service Pharmacologie-Toxicologie, Pôle de Biologie Territoriale, Reims, 51100, France
| | - Christine Terryn
- Université de Reims Champagne Ardenne, PICT, Reims, 51100, France
| | - Florine Dubuisson
- Université de Reims Champagne Ardenne, UR 3801 PPF, Reims, 51100, France
| | - Hervé Millart
- Université de Reims Champagne Ardenne, UR 3801 PPF, Reims, 51100, France
| | - Catherine Feliu
- Université de Reims Champagne Ardenne, UR 3801 PPF, Reims, 51100, France; Centre Hospitalier Universitaire de Reims, Service Pharmacologie-Toxicologie, Pôle de Biologie Territoriale, Reims, 51100, France
| | - Zoubir Djerada
- Université de Reims Champagne Ardenne, UR 3801 PPF, Reims, 51100, France; Centre Hospitalier Universitaire de Reims, Service Pharmacologie-Toxicologie, Pôle de Biologie Territoriale, Reims, 51100, France.
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12
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Lebek S, Caravia XM, Straub LG, Alzhanov D, Tan W, Li H, McAnally JR, Chen K, Xu L, Scherer PE, Liu N, Bassel-Duby R, Olson EN. CRISPR-Cas9 base editing of pathogenic CaMKIIδ improves cardiac function in a humanized mouse model. J Clin Invest 2024; 134:e175164. [PMID: 37856214 PMCID: PMC10760954 DOI: 10.1172/jci175164] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 10/17/2023] [Indexed: 10/21/2023] Open
Abstract
Cardiovascular diseases are the most common cause of worldwide morbidity and mortality, highlighting the necessity for advanced therapeutic strategies. Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) is a prominent inducer of various cardiac disorders, which is mediated by 2 oxidation-sensitive methionine residues within the regulatory domain. We have previously shown that ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing enables the heart to recover function from otherwise severe damage following ischemia/reperfusion (IR) injury. Here, we extended this therapeutic concept toward potential clinical translation. We generated a humanized CAMK2D knockin mouse model in which the genomic sequence encoding the entire regulatory domain was replaced with the human sequence. This enabled comparison and optimization of two different editing strategies for the human genome in mice. To edit CAMK2D in vivo, we packaged the optimized editing components into an engineered myotropic adeno-associated virus (MyoAAV 2A), which enabled efficient delivery at a very low AAV dose into the humanized mice at the time of IR injury. CAMK2D-edited mice recovered cardiac function, showed improved exercise performance, and were protected from myocardial fibrosis, which was otherwise observed in injured control mice after IR. Our findings identify a potentially effective strategy for cardioprotection in response to oxidative damage.
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Affiliation(s)
- Simon Lebek
- Department of Molecular Biology and
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Xurde M. Caravia
- Department of Molecular Biology and
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | | | - Damir Alzhanov
- Department of Molecular Biology and
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Wei Tan
- Department of Molecular Biology and
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Hui Li
- Department of Molecular Biology and
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - John R. McAnally
- Department of Molecular Biology and
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Kenian Chen
- Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Lin Xu
- Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | | | - Ning Liu
- Department of Molecular Biology and
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Rhonda Bassel-Duby
- Department of Molecular Biology and
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Eric N. Olson
- Department of Molecular Biology and
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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13
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Lebek S, Caravia XM, Chemello F, Tan W, McAnally JR, Chen K, Xu L, Liu N, Bassel-Duby R, Olson EN. Elimination of CaMKIIδ Autophosphorylation by CRISPR-Cas9 Base Editing Improves Survival and Cardiac Function in Heart Failure in Mice. Circulation 2023; 148:1490-1504. [PMID: 37712250 PMCID: PMC10842988 DOI: 10.1161/circulationaha.123.065117] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 08/22/2023] [Indexed: 09/16/2023]
Abstract
BACKGROUND Cardiovascular diseases are the main cause of worldwide morbidity and mortality, highlighting the need for new therapeutic strategies. Autophosphorylation and subsequent overactivation of the cardiac stress-responsive enzyme CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) serves as a central driver of multiple cardiac disorders. METHODS To develop a comprehensive therapy for heart failure, we used CRISPR-Cas9 adenine base editing to ablate the autophosphorylation site of CaMKIIδ. We generated mice harboring a phospho-resistant CaMKIIδ mutation in the germline and subjected these mice to severe transverse aortic constriction, a model for heart failure. Cardiac function, transcriptional changes, apoptosis, and fibrosis were assessed by echocardiography, RNA sequencing, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and standard histology, respectively. Specificity toward CaMKIIδ gene editing was assessed using deep amplicon sequencing. Cellular Ca2+ homeostasis was analyzed using epifluorescence microscopy in Fura-2-loaded cardiomyocytes. RESULTS Within 2 weeks after severe transverse aortic constriction surgery, 65% of all wild-type mice died, and the surviving mice showed dramatically impaired cardiac function. In contrast to wild-type mice, CaMKIIδ phospho-resistant gene-edited mice showed a mortality rate of only 11% and exhibited substantially improved cardiac function after severe transverse aortic constriction. Moreover, CaMKIIδ phospho-resistant mice were protected from heart failure-related aberrant changes in cardiac gene expression, myocardial apoptosis, and subsequent fibrosis, which were observed in wild-type mice after severe transverse aortic constriction. On the basis of identical mouse and human genome sequences encoding the autophosphorylation site of CaMKIIδ, we deployed the same editing strategy to modify this pathogenic site in human induced pluripotent stem cells. It is notable that we detected a >2000-fold increased specificity for editing of CaMKIIδ compared with other CaMKII isoforms, which is an important safety feature. While wild-type cardiomyocytes showed impaired Ca2+ transients and an increased frequency of arrhythmias after chronic β-adrenergic stress, CaMKIIδ-edited cardiomyocytes were protected from these adverse responses. CONCLUSIONS Ablation of CaMKIIδ autophosphorylation by adenine base editing may offer a potential broad-based therapeutic concept for human cardiac disease.
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Affiliation(s)
- Simon Lebek
- Department of Molecular Biology, University of Texas Southwestern Medical Center; Dallas, TX USA
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center; Dallas, TX USA
- Department of Internal Medicine II, University Hospital Regensburg; Regensburg, Germany
| | - Xurde M. Caravia
- Department of Molecular Biology, University of Texas Southwestern Medical Center; Dallas, TX USA
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center; Dallas, TX USA
| | - Francesco Chemello
- Department of Molecular Biology, University of Texas Southwestern Medical Center; Dallas, TX USA
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center; Dallas, TX USA
| | - Wei Tan
- Department of Molecular Biology, University of Texas Southwestern Medical Center; Dallas, TX USA
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center; Dallas, TX USA
| | - John R. McAnally
- Department of Molecular Biology, University of Texas Southwestern Medical Center; Dallas, TX USA
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center; Dallas, TX USA
| | - Kenian Chen
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center; Dallas, TX USA
| | - Lin Xu
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center; Dallas, TX USA
| | - Ning Liu
- Department of Molecular Biology, University of Texas Southwestern Medical Center; Dallas, TX USA
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center; Dallas, TX USA
| | - Rhonda Bassel-Duby
- Department of Molecular Biology, University of Texas Southwestern Medical Center; Dallas, TX USA
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center; Dallas, TX USA
| | - Eric N. Olson
- Department of Molecular Biology, University of Texas Southwestern Medical Center; Dallas, TX USA
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center; Dallas, TX USA
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14
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Zhang W, Dong E, Zhang J, Zhang Y. CaMKII, 'jack of all trades' in inflammation during cardiac ischemia/reperfusion injury. J Mol Cell Cardiol 2023; 184:48-60. [PMID: 37813179 DOI: 10.1016/j.yjmcc.2023.10.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 10/03/2023] [Accepted: 10/04/2023] [Indexed: 10/11/2023]
Abstract
Myocardial infarction and revascularization cause cardiac ischemia/reperfusion (I/R) injury featuring cardiomyocyte death and inflammation. The Ca2+/calmodulin dependent protein kinase II (CaMKII) family are serine/ threonine protein kinases that are involved in I/R injury. CaMKII exists in four different isoforms, α, β, γ, and δ. In the heart, CaMKII-δ is the predominant isoform，with multiple splicing variants, such as δB, δC and δ9. During I/R, elevated intracellular Ca2+ concentrations and reactive oxygen species activate CaMKII. In this review, we summarized the regulation and function of CaMKII in multiple cell types including cardiomyocytes, endothelial cells, and macrophages during I/R. We conclude that CaMKII mediates inflammation in the microenvironment of the myocardium, resulting in cell dysfunction, elevated inflammation, and cell death. However, different CaMKII-δ variants exhibit distinct or even opposite functions. Therefore, reagents/approaches that selectively target specific CaMKII isoforms and variants are needed for evaluating and counteracting the exact role of CaMKII in I/R injury and developing effective treatments against I/R injury.
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Affiliation(s)
- Wenjia Zhang
- State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China
| | - Erdan Dong
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China; Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing 100191, China; Haihe Laboratory of Cell Ecosystem, Beijing 100191, China
| | - Junxia Zhang
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China; Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing 100191, China; Haihe Laboratory of Cell Ecosystem, Beijing 100191, China.
| | - Yan Zhang
- State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
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15
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Chen S, Guan S, Yan Z, Ouyang F, Li S, Liu L, Zhong J. Role of RIPK3‑CaMKII‑mPTP signaling pathway‑mediated necroptosis in cardiovascular diseases (Review). Int J Mol Med 2023; 52:98. [PMID: 37654208 PMCID: PMC10495754 DOI: 10.3892/ijmm.2023.5301] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 07/27/2023] [Indexed: 09/02/2023] Open
Abstract
Necroptosis, which is distinct from apoptosis and necrosis, serves a crucial role in ontogeny and the maintenance of homeostasis. In the last decade, it has been demonstrated that the pathogenesis of cardiovascular diseases is also linked to necroptosis. Receptor interaction protein kinase (RIPK) 1, RIPK3 and mixed lineage kinase domain‑like protein serve vital roles in necroptosis. In addition to the aforementioned necroptosis‑related components, calcium/calmodulin‑dependent protein kinase II (CaMKII) has been identified as a novel substrate for RIPK3 that promotes the opening of the mitochondrial permeability transition pore (mPTP), and thus, mediates necroptosis of myocardial cells through the RIPK3‑CaMKII‑mPTP signaling pathway. The present review provides an overview of the current knowledge of the RIPK3‑CaMKII‑mPTP‑mediated necroptosis signaling pathway in cardiovascular diseases, focusing on the role of the RIPK3‑CaMKII‑mPTP signaling pathway in acute myocardial infarction, ischemia‑reperfusion injury, heart failure, abdominal aortic aneurysm, atherosclerosis, diabetic cardiomyopathy, hypertrophic cardiomyopathy, atrial fibrillation, and the cardiotoxicity associated with antitumor drugs and other chemicals. Finally, the present review discusses the research status of drugs targeting the RIPK3‑CaMKII‑mPTP signaling pathway.
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Affiliation(s)
- Sheng Chen
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, Guangdong 528308, P.R. China
| | - Senhong Guan
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, Guangdong 528308, P.R. China
| | - Zhaohan Yan
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, Guangdong 528308, P.R. China
| | - Fengshan Ouyang
- Department of Rehabilitation Medicine, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, Guangdong 528308, P.R. China
| | - Shuhuan Li
- Department of Pediatrics, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, Guangdong 528308, P.R. China
| | - Lanyuan Liu
- Department of Ultrasound Medicine, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, Guangdong 528308, P.R. China
| | - Jiankai Zhong
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, Guangdong 528308, P.R. China
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16
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Koval OM, Nguyen EK, Mittauer DJ, Ait-Aissa K, Chinchankar WC, Grumbach IM. Regulation of Smooth Muscle Cell Proliferation by Mitochondrial Ca2+ in Type 2 Diabetes. Int J Mol Sci 2023; 24:12897. [PMID: 37629079 PMCID: PMC10454141 DOI: 10.3390/ijms241612897] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 08/08/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Type 2 diabetes (T2D) is associated with increased risk of atherosclerotic vascular disease due to excessive vascular smooth muscle cell (VSMC) proliferation. Here, we investigated the role of mitochondrial dysfunction and Ca2+ levels in VSMC proliferation in T2D. VSMCs were isolated from normoglycemic and T2D-like mice induced by diet. The effects of mitochondrial Ca2+ uptake were studied using mice with selectively inhibited mitochondrial Ca2+/calmodulin-dependent kinase II (mtCaMKII) in VSMCs. Mitochondrial transition pore (mPTP) was blocked using ER-000444793. VSMCs from T2D compared to normoglycemic mice exhibited increased proliferation and baseline cytosolic Ca2+ levels ([Ca2+]cyto). T2D cells displayed lower endoplasmic reticulum Ca2+ levels, reduced mitochondrial Ca2+ entry, and increased Ca2+ leakage through the mPTP. Mitochondrial and cytosolic Ca2+ transients were diminished in T2D cells upon platelet-derived growth factor (PDGF) administration. Inhibiting mitochondrial Ca2+ uptake or the mPTP reduced VSMC proliferation in T2D, but had contrasting effects on [Ca2+]cyto. In T2D VSMCs, enhanced activation of Erk1/2 and its upstream regulators was observed, driven by elevated [Ca2+]cyto. Inhibiting mtCaMKII worsened the Ca2+ imbalance by blocking mitochondrial Ca2+ entry, leading to further increases in [Ca2+]cyto and Erk1/2 hyperactivation. Under these conditions, PDGF had no effect on VSMC proliferation. Inhibiting Ca2+-dependent signaling in the cytosol reduced excessive Erk1/2 activation and VSMC proliferation. Our findings suggest that altered Ca2+ handling drives enhanced VSMC proliferation in T2D, with mitochondrial dysfunction contributing to this process.
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Affiliation(s)
- Olha M. Koval
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Emily K. Nguyen
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Dylan J. Mittauer
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Karima Ait-Aissa
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - William C. Chinchankar
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Isabella M. Grumbach
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Fraternal Order of Eagles Diabetes Research Center, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
- Veterans Affairs Healthcare System, Iowa City, IA 52246, USA
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17
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Zheng M, Erhardt S, Cao Y, Wang J. Emerging Signaling Regulation of Sinoatrial Node Dysfunction. Curr Cardiol Rep 2023; 25:621-630. [PMID: 37227579 PMCID: PMC11418806 DOI: 10.1007/s11886-023-01885-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/14/2023] [Indexed: 05/26/2023]
Abstract
PURPOSE OF REVIEW The sinoatrial node (SAN), the natural pacemaker of the heart, is responsible for generating electrical impulses and initiating each heartbeat. Sinoatrial node dysfunction (SND) causes various arrhythmias such as sinus arrest, SAN block, and tachycardia/bradycardia syndrome. Unraveling the underlying mechanisms of SND is of paramount importance in the pursuit of developing effective therapeutic strategies for patients with SND. This review provides a concise summary of the most recent progress in the signaling regulation of SND. RECENT FINDINGS Recent studies indicate that SND can be caused by abnormal intercellular and intracellular signaling, various forms of heart failure (HF), and diabetes. These discoveries provide novel insights into the underlying mechanisms SND, advancing our understanding of its pathogenesis. SND can cause severe cardiac arrhythmias associated with syncope and an increased risk of sudden death. In addition to ion channels, the SAN is susceptible to the influence of various signalings including Hippo, AMP-activated protein kinase (AMPK), mechanical force, and natriuretic peptide receptors. New cellular and molecular mechanisms related to SND are also deciphered in systemic diseases such as HF and diabetes. Progress in these studies contributes to the development of potential therapeutics for SND.
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Affiliation(s)
- Mingjie Zheng
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Shannon Erhardt
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, The University of Texas, Houston, TX, 77030, USA
| | - Yuhan Cao
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Jun Wang
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, The University of Texas, Houston, TX, 77030, USA.
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18
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Ock S, Choi SW, Choi SH, Kang H, Kim SJ, Lee WS, Kim J. Insulin signaling is critical for sinoatrial node maintenance and function. Exp Mol Med 2023; 55:965-973. [PMID: 37121973 PMCID: PMC10238478 DOI: 10.1038/s12276-023-00988-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 02/12/2023] [Accepted: 02/12/2023] [Indexed: 05/02/2023] Open
Abstract
Insulin and insulin-like growth factor 1 (IGF-1) signaling regulate cellular growth and glucose metabolism in the myocardium. However, their physiological role in the cells of the cardiac conduction system has never been explored. Therefore, we sought to determine the spatiotemporal function of insulin/IGF-1 receptors in the sinoatrial node (SAN). We generated cardiac conduction cell-specific inducible IGF-1 receptor (IGF-1R) knockout (KO) (CSIGF1RKO), insulin receptor (IR) KO (CSIRKO), and IR/IGF-1R double-KO (CSDIRKO) mice and evaluated their phenotypes. Telemetric electrocardiography revealed regular sinus rhythm in CSIGF1RKO mice, indicating that IGF-1R is dispensable for normal pacemaking. In contrast, CSIRKO and CSDIRKO mice exhibited profound sinus bradycardia. CSDIRKO mice showed typical sinus node dysfunction characterized by junctional rhythm and sinus pauses on electrocardiography. Interestingly, the lack of an insulin receptor in the SAN cells of CSIRKO and CSDIRKO mice caused sinus nodal fibrosis. Mechanistically, hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) protein expression significantly decreased in the CSIRKO and CSDIRKO mice relative to the controls. A patch-clamp study of the SAN cells of CSIRKO mice revealed a significant decrease in the funny current, which is responsible for spontaneous diastolic depolarization in the SAN. This result suggested that insulin receptor loss reduces the heart rate via downregulation of the HCN4 channel. Additionally, HCN1 expression was decreased in CSDIRKO mice, explaining their sinus node dysfunction. Our results reveal a previously unrecognized role of insulin/IGF-1 signaling in sinus node structural maintenance and pacemaker function.
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Affiliation(s)
- Sangmi Ock
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Seong Woo Choi
- Departments of Physiology and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea
- Department of Physiology, Dongguk University College of Medicine, Gyeongju, Korea
| | - Seung Hee Choi
- Division of Endocrinology and Metabolism, Departments of Internal Medicine and Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu, Korea
| | - Hyun Kang
- Department of Anesthesiology, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Sung Joon Kim
- Departments of Physiology and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea
| | - Wang-Soo Lee
- Division of Cardiology, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea.
| | - Jaetaek Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea.
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Chaoul V, Hanna R, Hachem P, El Hayek MS, Nour‐Eldine W, Abou‐Khalil P, Abi‐Ramia E, Vandecasteele G, Abi‐Gerges A. Differential changes in cyclic adenosine 3′‐5′ monophosphate (
cAMP
) effectors and major Ca
2+
handling proteins during diabetic cardiomyopathy. J Cell Mol Med 2023; 27:1277-1289. [PMID: 36967707 PMCID: PMC10148055 DOI: 10.1111/jcmm.17733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 02/23/2023] [Accepted: 03/14/2023] [Indexed: 03/29/2023] Open
Abstract
Diabetic cardiomyopathy (DCM) is associated with differential and time-specific regulation of β-adrenergic receptors and cardiac cyclic nucleotide phosphodiesterases with consequences for total cyclic adenosine 3'-5' monophosphate (cAMP) levels. We aimed to investigate whether these changes are associated with downstream impairments in cAMP and Ca2+ signalling in a type 1 diabetes (T1D)-induced DCM model. T1D was induced in adult male rats by streptozotocin (65 mg/kg) injection. DCM was assessed by cardiac structural and molecular remodelling. We delineated sequential changes affecting the exchange protein (Epac1/2), cAMP-dependent protein kinase A (PKA) and Ca2+ /Calmodulin-dependent kinase II (CaMKII) at 4, 8 and 12 weeks following diabetes, by real-time quantitative PCR and western blot. Expression of Ca2+ ATPase pump (SERCA2a), phospholamban (PLB) and Troponin I (TnI) was also examined. Early upregulation of Epac1 transcripts was noted in diabetic hearts at Week 4, followed by increases in Epac2 mRNA, but not protein levels, at Week 12. Expression of PKA subunits (RI, RIIα and Cα) remained unchanged regardless of the disease stage, whereas CaMKII increased at Week 12 in DCM. Moreover, PLB transcripts were upregulated in diabetic hearts, whereas SERCA2a and TnI gene expression was unchanged irrespective of the disease evolution. PLB phosphorylation at threonine-17 was increased in DCM, whereas phosphorylation of both PLB at serine-16 and TnI at serine-23/24 was unchanged. We show for the first time differential and time-specific regulations in cardiac cAMP effectors and Ca2+ handling proteins, data that may prove useful in proposing new therapeutic approaches in T1D-induced DCM.
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Affiliation(s)
- Victoria Chaoul
- Gilbert and Rose‐Marie Chagoury School of MedicineLebanese American UniversityP.O. Box 36ByblosLebanon
| | - Rita Hanna
- Gilbert and Rose‐Marie Chagoury School of MedicineLebanese American UniversityP.O. Box 36ByblosLebanon
| | - Pia Hachem
- Gilbert and Rose‐Marie Chagoury School of MedicineLebanese American UniversityP.O. Box 36ByblosLebanon
| | - Magali Samia El Hayek
- Signaling and Cardiovascular Pathophysiology, UMR‐S1180Université Paris‐SaclayOrsay91400France
| | - Wared Nour‐Eldine
- Gilbert and Rose‐Marie Chagoury School of MedicineLebanese American UniversityP.O. Box 36ByblosLebanon
| | - Pamela Abou‐Khalil
- Gilbert and Rose‐Marie Chagoury School of MedicineLebanese American UniversityP.O. Box 36ByblosLebanon
| | - Elias Abi‐Ramia
- School of Arts and Sciences, Department of Natural SciencesLebanese American UniversityByblosLebanon
| | - Grégoire Vandecasteele
- Signaling and Cardiovascular Pathophysiology, UMR‐S1180Université Paris‐SaclayOrsay91400France
| | - Aniella Abi‐Gerges
- Gilbert and Rose‐Marie Chagoury School of MedicineLebanese American UniversityP.O. Box 36ByblosLebanon
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20
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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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21
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Koval OM, Nguyen EK, Mittauer DJ, Ait-Aissa K, Chinchankar W, Qian L, Madesh M, Dai DF, Grumbach IM. The mitochondrial regulation of smooth muscle cell proliferation in type 2 diabetes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.15.528765. [PMID: 36824758 PMCID: PMC9948984 DOI: 10.1101/2023.02.15.528765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
Background Type 2 diabetes (T2D) is associated with a strongly increased risk for restenosis after angioplasty driven by proliferation of vascular smooth muscle cells (VSMCs). Here, we sought to determine whether and how mitochondrial dysfunction in T2D drives VSMC proliferation with a focus on ROS and intracellular [Ca 2+ ] that both drive cell proliferation, occur in T2D and are regulated by mitochondrial activity. Methods Using a diet-induced mouse model of T2D, the inhibition of the mitochondrial Ca 2+ /calmodulin-dependent kinase II (mtCaMKII), a regulator of Ca 2+ entry via the mitochondrial Ca 2+ uniporter selectively in VSMCs, we performed in vivo phenotyping after mechanical injury and established the mechanisms of excessive proliferation in cultured VSMCs. Results In T2D, the inhibition of mtCaMKII reduced both neointima formation after mechanical injury and the proliferation of cultured VSMCs. VSMCs from T2D mice displayed accelerated proliferation, reduced mitochondrial Ca 2+ entry and membrane potential with elevated baseline [Ca 2+ ] cyto compared to cells from normoglycemic mice. Accelerated proliferation after PDGF treatment was driven by activation of Erk1/2 and its upstream regulators. Hyperactivation of Erk1/2 was Ca 2+ -dependent rather than mitochondrial ROS-driven Ca 2+ -dependent and included the activation of CaMKII in the cytosol. The inhibition of mtCaMKII exaggerated the Ca 2+ imbalance by lowering mitochondrial Ca 2+ entry and increasing baseline [Ca 2+ ] cyto , further enhancing baseline Erk1/2 activation. With inhibition of mtCaMKII, PDGF treatment had no additional effect on cell proliferation. Inhibition of activated CaMKII in the cytosol decreased excessive Erk1/2 activation and reduced VSMC proliferation. Conclusions Collectively, our results provide evidence for the molecular mechanisms of enhanced VSMC proliferation after mechanical injury by mitochondrial Ca 2+ entry in T2D.
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Affiliation(s)
- Olha M. Koval
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
| | - Emily K. Nguyen
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
| | - Dylan J. Mittauer
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
| | - Karima Ait-Aissa
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
| | - William Chinchankar
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
| | - Lan Qian
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
| | - Muniswamy Madesh
- Center for Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Texas Health San Antonio, San Antonio, Texas 78229, USA
| | - Dao-Fu Dai
- Division of Pathology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
| | - Isabella M. Grumbach
- Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City IA 52242, USA
- Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City IA 52242, USA
- Veterans Affairs Healthcare System, Iowa City, IA 52246, USA
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22
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Haugsten Hansen M, Sadredini M, Hasic A, Anderson ME, Sjaastad I, Korseberg Stokke M. CaMKII and reactive oxygen species contribute to early reperfusion arrhythmias, but oxidation of CaMKIIδ at methionines 281/282 is not a determining factor. J Mol Cell Cardiol 2023; 175:49-61. [PMID: 36528076 DOI: 10.1016/j.yjmcc.2022.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 12/07/2022] [Accepted: 12/12/2022] [Indexed: 12/16/2022]
Abstract
BACKGROUND Available evidence suggest that Ca2+/calmodulin-dependent protein kinase type IIδ (CaMKIIδ) and reactive oxygen species (ROS) are important in early ischemia-reperfusion arrhythmias (IRA). Since ROS can activate CaMKIIδ by oxidation of two methionines at positions 281/282, oxidized-CaMKIIδ (Ox-CaMKIIδ) has been proposed to be important for IRA. However, direct evidence for this is missing. METHODS We exposed Langendorff-perfused hearts and ventricular cardiomyocytes from C57BL/6 mice to global and simulated ischemia, respectively, and recorded arrhythmic events during early reperfusion. Hearts were collected for immunoblotting of key phosphoproteins. We evaluated the effects of beta-adrenoceptor stimulation, inhibition of CaMKII, and reduced ROS levels with isoprenaline, KN93/AIP and N-acetylcysteine (NAC), respectively. We further tested the importance of Ox-CaMKIIδ by using hearts and cardiomyocytes from mice with CaMKIIδ resistant to oxidation of methionines 281 and 282 (MMVV). RESULTS Hearts treated with KN93, AIP or NAC had lower incidence of early IRA, and NAC-treated cardiomyocytes had lower incidence of arrhythmogenic events. However, hearts from MMVV mice had a similar incidence of early IRA to wild type mice (WT), and MMVV and WT cardiomyocytes had a similar frequency of Ca2+ waves and Ca2+ sparks. Immunoblotting confirmed high levels of oxidation in early reperfusion, but revealed no significant differences in the phosphorylation levels of Ca2+-handling proteins in MMVV and WT hearts. CONCLUSIONS Although CaMKII and ROS both contribute to early IRA, hearts from mice with CaMKII resistant to oxidation at methionines 281/282 were not protected from such arrhythmias, suggesting that oxidation at these sites is not a determining factor.
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Affiliation(s)
- Marie Haugsten Hansen
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; KG Jebsen Centre for Cardiac Research, University of Oslo, Oslo, Norway
| | - Mani Sadredini
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; KG Jebsen Centre for Cardiac Research, University of Oslo, Oslo, Norway
| | - Almira Hasic
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; KG Jebsen Centre for Cardiac Research, University of Oslo, Oslo, Norway
| | - Mark E Anderson
- Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ivar Sjaastad
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; KG Jebsen Centre for Cardiac Research, University of Oslo, Oslo, Norway
| | - Mathis Korseberg Stokke
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; KG Jebsen Centre for Cardiac Research, University of Oslo, Oslo, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
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23
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Hegner P, Lebek S, Schaner B, Ofner F, Gugg M, Maier LS, Arzt M, Wagner S. CaMKII-Dependent Contractile Dysfunction and Pro-Arrhythmic Activity in a Mouse Model of Obstructive Sleep Apnea. Antioxidants (Basel) 2023; 12:antiox12020315. [PMID: 36829874 PMCID: PMC9952298 DOI: 10.3390/antiox12020315] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Left ventricular contractile dysfunction and arrhythmias frequently occur in patients with sleep-disordered breathing (SDB). The CaMKII-dependent dysregulation of cellular Ca homeostasis has recently been described in SDB patients, but these studies only partly explain the mechanism and are limited by the patients' heterogeneity. Here, we analyzed contractile function and Ca homeostasis in a mouse model of obstructive sleep apnea (OSA) that is not limited by confounding comorbidities. OSA was induced by artificial tongue enlargement with polytetrafluorethylene (PTFE) injection into the tongue of wildtype mice and mice with a genetic ablation of the oxidative activation sites of CaMKII (MMVV knock-in). After eight weeks, cardiac function was assessed with echocardiography. Reactive oxygen species (ROS) and Ca transients were measured using confocal and epifluorescence microscopy, respectively. Wildtype PTFE mice exhibited an impaired ejection fraction, while MMVV PTFE mice were fully protected. As expected, isolated cardiomyocytes from PTFE mice showed increased ROS production. We further observed decreased levels of steady-state Ca transients, decreased levels of caffeine-induced Ca transients, and increased pro-arrhythmic activity (defined as deviations from the diastolic Ca baseline) only in wildtype but not in MMVV PTFE mice. In summary, in the absence of any comorbidities, OSA was associated with contractile dysfunction and pro-arrhythmic activity and the inhibition of the oxidative activation of CaMKII conveyed cardioprotection, which may have therapeutic implications.
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Affiliation(s)
- Philipp Hegner
- Department of Internal Medicine II, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Simon Lebek
- Department of Internal Medicine II, University Hospital Regensburg, 93053 Regensburg, Germany
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Benedikt Schaner
- Department of Internal Medicine II, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Florian Ofner
- Department of Internal Medicine II, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Mathias Gugg
- Department of Internal Medicine II, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Lars Siegfried Maier
- Department of Internal Medicine II, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Michael Arzt
- Department of Internal Medicine II, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Stefan Wagner
- Department of Internal Medicine II, University Hospital Regensburg, 93053 Regensburg, Germany
- Correspondence:
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24
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Lebek S, Chemello F, Caravia XM, Tan W, Li H, Chen K, Xu L, Liu N, Bassel-Duby R, Olson EN. Ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing as a therapy for cardiac disease. Science 2023; 379:179-185. [PMID: 36634166 PMCID: PMC10150399 DOI: 10.1126/science.ade1105] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
CRISPR-Cas9 gene editing is emerging as a prospective therapy for genomic mutations. However, current editing approaches are directed primarily toward relatively small cohorts of patients with specific mutations. Here, we describe a cardioprotective strategy potentially applicable to a broad range of patients with heart disease. We used base editing to ablate the oxidative activation sites of CaMKIIδ, a primary driver of cardiac disease. We show in cardiomyocytes derived from human induced pluripotent stem cells that editing the CaMKIIδ gene to eliminate oxidation-sensitive methionine residues confers protection from ischemia/reperfusion (IR) injury. Moreover, CaMKIIδ editing in mice at the time of IR enables the heart to recover function from otherwise severe damage. CaMKIIδ gene editing may thus represent a permanent and advanced strategy for heart disease therapy.
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Affiliation(s)
- Simon Lebek
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.,Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.,Department of Internal Medicine II, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Francesco Chemello
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.,Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xurde M Caravia
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.,Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Wei Tan
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.,Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Hui Li
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.,Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Kenian Chen
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Lin Xu
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ning Liu
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.,Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Rhonda Bassel-Duby
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.,Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Eric N Olson
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.,Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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25
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Ricci E, Bartolucci C, Severi S. The virtual sinoatrial node: What did computational models tell us about cardiac pacemaking? PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 177:55-79. [PMID: 36374743 DOI: 10.1016/j.pbiomolbio.2022.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 10/17/2022] [Accepted: 10/24/2022] [Indexed: 11/11/2022]
Abstract
Since its discovery, the sinoatrial node (SAN) has represented a fascinating and complex matter of research. Despite over a century of discoveries, a full comprehension of pacemaking has still to be achieved. Experiments often produced conflicting evidence that was used either in support or against alternative theories, originating intense debates. In this context, mathematical descriptions of the phenomena underlying the heartbeat have grown in importance in the last decades since they helped in gaining insights where experimental evaluation could not reach. This review presents the most updated SAN computational models and discusses their contribution to our understanding of cardiac pacemaking. Electrophysiological, structural and pathological aspects - as well as the autonomic control over the SAN - are taken into consideration to reach a holistic view of SAN activity.
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Affiliation(s)
- Eugenio Ricci
- Department of Electrical, Electronic, and Information Engineering "Guglielmo Marconi", University of Bologna, Cesena (FC), Italy
| | - Chiara Bartolucci
- Department of Electrical, Electronic, and Information Engineering "Guglielmo Marconi", University of Bologna, Cesena (FC), Italy
| | - Stefano Severi
- Department of Electrical, Electronic, and Information Engineering "Guglielmo Marconi", University of Bologna, Cesena (FC), Italy.
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26
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Chen Y, Lu Y, Wu W, Lin Y, Chen Y, Chen S, Chen Y. Advanced glycation end products modulate electrophysiological remodeling of right ventricular outflow tract cardiomyocytes: A novel target for diabetes-related ventricular arrhythmogenesis. Physiol Rep 2022; 10:e15499. [PMID: 36325589 PMCID: PMC9630757 DOI: 10.14814/phy2.15499] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 09/11/2022] [Accepted: 10/08/2022] [Indexed: 06/16/2023] Open
Abstract
Diabetes mellitus is associated with cardiovascular disease and cardiac arrhythmia. Accumulation of advanced glycation end products closely correlates with cardiovascular complications through mitochondrial dysfunction or oxidative stress and evoke proliferative, inflammatory, and fibrotic reactions, which might impair cardiac electrophysiological characteristics and increase the incidence of cardiac arrhythmia. This study examined the mechanisms how advanced glycation end products may contribute to arrhythmogenesis of right ventricular outflow tract-a unique arrhythmogenic substrate. A whole-cell patch clamp, conventional electrophysiological study, fluorescence imaging, Western blot, and confocal microscope were used to study the electrical activity, and Ca2+ homeostasis or signaling in isolated right ventricular outflow tract myocytes with and without advanced glycation end products (100 μg/ml). The advanced glycation end products treated right ventricular outflow tract myocytes had a similar action potential duration as the controls, but exhibited a lower L-type Ca2+ current, higher late sodium current and transient outward current. Moreover, the advanced glycation end products treated right ventricular outflow tract myocytes had more intracellular Na+ , reverse mode Na+ -Ca2+ exchanger currents, intracellular and mitochondrial reactive oxygen species, and less intracellular Ca2+ transient and sarcoplasmic reticulum Ca2+ content with upregulated calcium homeostasis proteins and advanced glycation end products related signaling pathway proteins. In conclusions, advanced glycation end products modulate right ventricular outflow tract electrophysiological characteristics with larger late sodium current, intracellular Na+ , reverse mode Na+ -Ca2+ exchanger currents, and disturbed Ca2+ homeostasis through increased oxidative stress mediated by the activation of the advanced glycation end products signaling pathway.
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Affiliation(s)
- Yao‐Chang Chen
- Department of Biomedical EngineeringNational Defense Medical CenterTaipeiTaiwan
| | - Yen‐Yu Lu
- Division of CardiologySijhih Cathay General HospitalNew Taipei CityTaiwan
- School of Medicine, College of MedicineFu Jen Catholic UniversityNew Taipei CityTaiwan
| | - Wen‐Shiann Wu
- Department of CardiologyChi‐Mei Medical CenterTainanTaiwan
| | - Yung‐Kuo Lin
- Taipei Heart Institute, Taipei Medical UniversityTaipeiTaiwan
- Division of Cardiovascular Medicine, Department of Internal MedicineWan Fang Hospital, Taipei Medical UniversityTaipeiTaiwan
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
| | - Yi‐Ann Chen
- Division of CardiologySijhih Cathay General HospitalNew Taipei CityTaiwan
- Division of NephrologySijhih Cathay General HospitalNew Taipei CityTaiwan
| | - Shih‐Ann Chen
- Heart Rhythm Center, Division of Cardiology, Department of MedicineTaipei Veterans General HospitalTaipeiTaiwan
- Cardiovascular Center, Taichung Veterans General HospitalTaichungTaiwan
- Department of Post‐Baccalaureate Medicine, College of MedicineNational Chung Hsing UniversityTaichungTaiwan
| | - Yi‐Jen Chen
- Taipei Heart Institute, Taipei Medical UniversityTaipeiTaiwan
- Division of Cardiovascular Medicine, Department of Internal MedicineWan Fang Hospital, Taipei Medical UniversityTaipeiTaiwan
- Graduate Institute of Clinical Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
- Cardiovascular Research CenterWan Fang Hospital, Taipei Medical UniversityTaipeiTaiwan
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27
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Luo A, Xie Z, Wang Y, Wang X, Li S, Yan J, Zhan G, Zhou Z, Zhao Y, Li S. Type 2 diabetes mellitus-associated cognitive dysfunction: Advances in potential mechanisms and therapies. Neurosci Biobehav Rev 2022; 137:104642. [PMID: 35367221 DOI: 10.1016/j.neubiorev.2022.104642] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 03/24/2022] [Accepted: 03/27/2022] [Indexed: 12/22/2022]
Abstract
Type 2 diabetes (T2D) and its target organ injuries cause distressing impacts on personal health and put an enormous burden on the healthcare system, and increasing attention has been paid to T2D-associated cognitive dysfunction (TDACD). TDACD is characterized by cognitive dysfunction, delayed executive ability, and impeded information-processing speed. Brain imaging data suggest that extensive brain regions are affected in patients with T2D. Based on current findings, a wide spectrum of non-specific neurodegenerative mechanisms that partially overlap with the mechanisms of neurodegenerative diseases is hypothesized to be associated with TDACD. However, it remains unclear whether TDACD is a consequence of T2D or a complication that co-occurs with T2D. Theoretically, anti-diabetes methods are promising neuromodulatory approaches to reduce brain injury in patients with T2D. In this review, we summarize potential mechanisms underlying TDACD and promising neurotropic effects of anti-diabetes methods and some neuroprotective natural compounds. Constructing screening or diagnostic tools and developing targeted treatment and preventive strategies would be expected to reduce the burden of TDACD.
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Affiliation(s)
- Ailin Luo
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Zheng Xie
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Yue Wang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Xuan Wang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Shan Li
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Jing Yan
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Gaofeng Zhan
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Zhiqiang Zhou
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Yilin Zhao
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Shiyong Li
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
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28
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Gömöri K, Herwig M, Budde H, Hassoun R, Mostafi N, Zhazykbayeva S, Sieme M, Modi S, Szabados T, Pipis J, Farkas-Morvay N, Leprán I, Ágoston G, Baczkó I, Kovács Á, Mügge A, Ferdinandy P, Görbe A, Bencsik P, Hamdani N. Ca2+/calmodulin-dependent protein kinase II and protein kinase G oxidation contributes to impaired sarcomeric proteins in hypertrophy model. ESC Heart Fail 2022; 9:2585-2600. [PMID: 35584900 PMCID: PMC9288768 DOI: 10.1002/ehf2.13973] [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: 03/02/2022] [Revised: 04/20/2022] [Accepted: 05/04/2022] [Indexed: 11/24/2022] Open
Abstract
Aims Volume overload (VO) induced hypertrophy is one of the hallmarks to the development of heart diseases. Understanding the compensatory mechanisms involved in this process might help preventing the disease progression. Methods and results Therefore, the present study used 2 months old Wistar rats, which underwent an aortocaval fistula to develop VO‐induced hypertrophy. The animals were subdivided into four different groups, two sham operated animals served as age‐matched controls and two groups with aortocaval fistula. Echocardiography was performed prior termination after 4‐ and 8‐month. Functional and molecular changes of several sarcomeric proteins and their signalling pathways involved in the regulation and modulation of cardiomyocyte function were investigated. Results The model was characterized with preserved ejection fraction in all groups and with elevated heart/body weight ratio, left/right ventricular and atrial weight at 4‐ and 8‐month, which indicates VO‐induced hypertrophy. In addition, 8‐months groups showed increased left ventricular internal diameter during diastole, RV internal diameter, stroke volume and velocity‐time index compared with their age‐matched controls. These changes were accompanied by increased Ca2+ sensitivity and titin‐based cardiomyocyte stiffness in 8‐month VO rats compared with other groups. The altered cardiomyocyte mechanics was associated with phosphorylation deficit of sarcomeric proteins cardiac troponin I, myosin binding protein C and titin, also accompanied with impaired signalling pathways involved in phosphorylation of these sarcomeric proteins in 8‐month VO rats compared with age‐matched control group. Impaired protein phosphorylation status and dysregulated signalling pathways were associated with significant alterations in the oxidative status of both kinases CaMKII and PKG explaining by this the elevated Ca2+ sensitivity and titin‐based cardiomyocyte stiffness and perhaps the development of hypertrophy. Conclusions Our findings showed VO‐induced cardiomyocyte dysfunction via deranged phosphorylation of myofilament proteins and signalling pathways due to increased oxidative state of CaMKII and PKG and this might contribute to the development of hypertrophy.
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Affiliation(s)
- Kamilla Gömöri
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.,Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.,Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Melissa Herwig
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.,Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Heidi Budde
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.,Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Roua Hassoun
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.,Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Nusratul Mostafi
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.,Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Saltanat Zhazykbayeva
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.,Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Marcel Sieme
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.,Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Suvasini Modi
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.,Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Tamara Szabados
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.,Pharmahungary Group, Szeged, Hungary
| | - Judit Pipis
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.,Pharmahungary Group, Szeged, Hungary
| | | | - István Leprán
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
| | - Gergely Ágoston
- Institute of Family Medicine, University of Szeged, Szeged, Hungary
| | - István Baczkó
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
| | - Árpád Kovács
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.,Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Andreas Mügge
- Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,Pharmahungary Group, Szeged, Hungary
| | - Anikó Görbe
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.,Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,Pharmahungary Group, Szeged, Hungary
| | - Péter Bencsik
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.,Pharmahungary Group, Szeged, Hungary
| | - Nazha Hamdani
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.,Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany.,HCEMM-Cardiovascular Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
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Enhanced Cardiac CaMKII Oxidation and CaMKII-Dependent SR Ca Leak in Patients with Sleep-Disordered Breathing. Antioxidants (Basel) 2022; 11:antiox11020331. [PMID: 35204213 PMCID: PMC8868143 DOI: 10.3390/antiox11020331] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/26/2022] [Accepted: 02/07/2022] [Indexed: 02/04/2023] Open
Abstract
Background: Sleep-disordered breathing (SDB) is associated with increased oxidant generation. Oxidized Ca/calmodulin kinase II (CaMKII) can contribute to atrial arrhythmias by the stimulation of sarcoplasmic reticulum Ca release events, i.e., Ca sparks. Methods: We prospectively enrolled 39 patients undergoing cardiac surgery to screen for SDB and collected right atrial appendage biopsies. Results: SDB was diagnosed in 14 patients (36%). SDB patients had significantly increased levels of oxidized and activated CaMKII (assessed by Western blotting/specific pulldown). Moreover, SDB patients showed a significant increase in Ca spark frequency (CaSpF measured by confocal microscopy) compared with control subjects. CaSpF was 3.58 ± 0.75 (SDB) vs. 2.49 ± 0.84 (no SDB) 1/100 µm−1s−1 (p < 0.05). In linear multivariable regression models, SDB severity was independently associated with increased CaSpF (B [95%CI]: 0.05 [0.03; 0.07], p < 0.001) after adjusting for important comorbidities. Interestingly, 30 min exposure to the CaMKII inhibitor autocamtide-2 related autoinhibitory peptide normalized the increased CaSpF and eliminated the association between SDB and CaSpF (B [95%CI]: 0.01 [−0.1; 0.03], p = 0.387). Conclusions: Patients with SDB have increased CaMKII oxidation/activation and increased CaMKII-dependent CaSpF in the atrial myocardium, independent of major clinical confounders, which may be a novel target for treatment of atrial arrhythmias in SDB.
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30
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Lang D, Medvedev RY, Ratajczyk L, Zheng J, Yuan X, Lim E, Han OY, Valdivia HH, Glukhov AV. Region-specific distribution of transversal-axial tubule system organization underlies heterogeneity of calcium dynamics in the right atrium. Am J Physiol Heart Circ Physiol 2022; 322:H269-H284. [PMID: 34951544 PMCID: PMC8782648 DOI: 10.1152/ajpheart.00381.2021] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The atrial myocardium demonstrates the highly heterogeneous organization of the transversal-axial tubule system (TATS), although its anatomical distribution and region-specific impact on Ca2+ dynamics remain unknown. Here, we developed a novel method for high-resolution confocal imaging of TATS in intact live mouse atrial myocardium and applied a custom-developed MATLAB-based computational algorithm for the automated analysis of TATS integrity. We observed a twofold higher (P < 0.01) TATS density in the right atrial appendage (RAA) than in the intercaval regions (ICR, the anatomical region between the superior vena cava and atrioventricular junction and between the crista terminalis and interatrial septum). Whereas RAA predominantly consisted of well-tubulated myocytes, ICR showed partially tubulated/untubulated cells. Similar TATS distribution was also observed in healthy human atrial myocardium sections. In both mouse atrial preparations and isolated mouse atrial myocytes, we observed a strong anatomical correlation between TATS distribution and Ca2+ transient synchronization and rise-up time. This region-specific difference in Ca2+ transient morphology disappeared after formamide-induced detubulation. ICR myocytes showed a prolonged action potential duration at 80% of repolarization as well as a significantly lower expression of RyR2 and Cav1.2 proteins but similar levels of NCX1 and Cav1.3 compared with RAA tissue. Our findings provide a detailed characterization of the region-specific distribution of TATS in mouse and human atrial myocardium, highlighting the structural foundation for anatomical heterogeneity of Ca2+ dynamics and contractility in the atria. These results could indicate different roles of TATS in Ca2+ signaling at distinct anatomical regions of the atria and provide mechanistic insight into pathological atrial remodeling.NEW & NOTEWORTHY Mouse and human atrial myocardium demonstrate high variability in the organization of the transversal-axial tubule system (TATS), with more organized TATS expressed in the right atrial appendage. TATS distribution governs anatomical heterogeneity of Ca2+ dynamics and thus could contribute to integral atrial contractility, mechanics, and arrhythmogenicity.
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Affiliation(s)
- Di Lang
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin
| | - Roman Y Medvedev
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin
| | - Lucas Ratajczyk
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin
| | - Jingjing Zheng
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin
| | - Xiaoyu Yuan
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin
| | - Evi Lim
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin
| | - Owen Y Han
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin
| | - Hector H Valdivia
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin
| | - Alexey V Glukhov
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin
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31
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Zhang M, Zhang J, Zhang W, Hu Q, Jin L, Xie P, Zheng W, Shang H, Zhang Y. CaMKII-δ9 Induces Cardiomyocyte Death to Promote Cardiomyopathy and Heart Failure. Front Cardiovasc Med 2022; 8:820416. [PMID: 35127874 PMCID: PMC8811042 DOI: 10.3389/fcvm.2021.820416] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 12/21/2021] [Indexed: 01/11/2023] Open
Abstract
Heart failure is a syndrome in which the heart cannot pump enough blood to meet the body's needs, resulting from impaired ventricular filling or ejection of blood. Heart failure is still a global public health problem and remains a substantial unmet medical need. Therefore, it is crucial to identify new therapeutic targets for heart failure. Ca2+/calmodulin-dependent kinase II (CaMKII) is a serine/threonine protein kinase that modulates various cardiac diseases. CaMKII-δ9 is the most abundant CaMKII-δ splice variant in the human heart and acts as a central mediator of DNA damage and cell death in cardiomyocytes. Here, we proved that CaMKII-δ9 mediated cardiomyocyte death promotes cardiomyopathy and heart failure. However, CaMKII-δ9 did not directly regulate cardiac hypertrophy. Furthermore, we also showed that CaMKII-δ9 induced cell death in adult cardiomyocytes through impairing the UBE2T/DNA repair signaling. Finally, we demonstrated no gender difference in the expression of CaMKII-δ9 in the hearts, together with its related cardiac pathology. These findings deepen our understanding of the role of CaMKII-δ9 in cardiac pathology and provide new insights into the mechanisms and therapy of heart failure.
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Affiliation(s)
- Mao Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
| | - Junxia Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
| | - Wenjia Zhang
- Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Institute of Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
| | - Qingmei Hu
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
| | - Li Jin
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
| | - Peng Xie
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
| | - Wen Zheng
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
| | - Haibao Shang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
| | - Yan Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Institute of Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
- *Correspondence: Yan Zhang
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32
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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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33
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Al Kury LT, Chacar S, Alefishat E, Khraibi AA, Nader M. Structural and Electrical Remodeling of the Sinoatrial Node in Diabetes: New Dimensions and Perspectives. Front Endocrinol (Lausanne) 2022; 13:946313. [PMID: 35872997 PMCID: PMC9302195 DOI: 10.3389/fendo.2022.946313] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 06/14/2022] [Indexed: 11/14/2022] Open
Abstract
The sinoatrial node (SAN) is composed of highly specialized cells that mandate the spontaneous beating of the heart through self-generation of an action potential (AP). Despite this automaticity, the SAN is under the modulation of the autonomic nervous system (ANS). In diabetes mellitus (DM), heart rate variability (HRV) manifests as a hallmark of diabetic cardiomyopathy. This is paralleled by an impaired regulation of the ANS, and by a pathological remodeling of the pacemaker structure and function. The direct effect of diabetes on the molecular signatures underscoring this pathology remains ill-defined. The recent focus on the electrical currents of the SAN in diabetes revealed a repressed firing rate of the AP and an elongation of its tracing, along with conduction abnormalities and contractile failure. These changes are blamed on the decreased expression of ion transporters and cell-cell communication ports at the SAN (i.e., HCN4, calcium and potassium channels, connexins 40, 45, and 46) which further promotes arrhythmias. Molecular analysis crystallized the RGS4 (regulator of potassium currents), mitochondrial thioredoxin-2 (reactive oxygen species; ROS scavenger), and the calcium-dependent calmodulin kinase II (CaMKII) as metabolic culprits of relaying the pathological remodeling of the SAN cells (SANCs) structure and function. A special attention is given to the oxidation of CaMKII and the generation of ROS that induce cell damage and apoptosis of diabetic SANCs. Consequently, the diabetic SAN contains a reduced number of cells with significant infiltration of fibrotic tissues that further delay the conduction of the AP between the SANCs. Failure of a genuine generation of AP and conduction of their derivative waves to the neighboring atrial myocardium may also occur as a result of the anti-diabetic regiment (both acute and/or chronic treatments). All together, these changes pose a challenge in the field of cardiology and call for further investigations to understand the etiology of the structural/functional remodeling of the SANCs in diabetes. Such an understanding may lead to more adequate therapies that can optimize glycemic control and improve health-related outcomes in patients with diabetes.
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Affiliation(s)
- Lina T. Al Kury
- Department of Health Sciences, College of Natural and Health Sciences, Zayed University, Abu Dhabi, United Arab Emirates
- *Correspondence: Lina T. Al Kury, ; Moni Nader,
| | - Stephanie Chacar
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Eman Alefishat
- Department of Pharmacology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
- Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, The University of Jordan, Amman, Jordan
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Ali A. Khraibi
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Moni Nader
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
- *Correspondence: Lina T. Al Kury, ; Moni Nader,
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34
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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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35
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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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36
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Hamilton S, Terentyeva R, Perger F, Hernández Orengo B, Martin B, Gorr MW, Belevych AE, Clements RT, Györke S, Terentyev D. MCU overexpression evokes disparate dose-dependent effects on mito-ROS and spontaneous Ca 2+ release in hypertrophic rat cardiomyocytes. Am J Physiol Heart Circ Physiol 2021; 321:H615-H632. [PMID: 34415186 PMCID: PMC8794228 DOI: 10.1152/ajpheart.00126.2021] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 08/13/2021] [Accepted: 08/13/2021] [Indexed: 12/11/2022]
Abstract
Cardiac dysfunction in heart failure (HF) and diabetic cardiomyopathy (DCM) is associated with aberrant intracellular Ca2+ handling and impaired mitochondrial function accompanied with reduced mitochondrial calcium concentration (mito-[Ca2+]). Pharmacological or genetic facilitation of mito-Ca2+ uptake was shown to restore Ca2+ transient amplitude in DCM and HF, improving contractility. However, recent reports suggest that pharmacological enhancement of mito-Ca2+ uptake can exacerbate ryanodine receptor-mediated spontaneous sarcoplasmic reticulum (SR) Ca2+ release in ventricular myocytes (VMs) from diseased animals, increasing propensity to stress-induced ventricular tachyarrhythmia. To test whether chronic recovery of mito-[Ca2+] restores systolic Ca2+ release without adverse effects in diastole, we overexpressed mitochondrial Ca2+ uniporter (MCU) in VMs from male rat hearts with hypertrophy induced by thoracic aortic banding (TAB). Measurement of mito-[Ca2+] using genetic probe mtRCamp1h revealed that mito-[Ca2+] in TAB VMs paced at 2 Hz under β-adrenergic stimulation is lower compared with shams. Adenoviral 2.5-fold MCU overexpression in TAB VMs fully restored mito-[Ca2+]. However, it failed to improve cytosolic Ca2+ handling and reduce proarrhythmic spontaneous Ca2+ waves. Furthermore, mitochondrial-targeted genetic probes MLS-HyPer7 and OMM-HyPer revealed a significant increase in emission of reactive oxygen species (ROS) in TAB VMs with 2.5-fold MCU overexpression. Conversely, 1.5-fold MCU overexpression in TABs, that led to partial restoration of mito-[Ca2+], reduced mitochondria-derived reactive oxygen species (mito-ROS) and spontaneous Ca2+ waves. Our findings emphasize the key role of elevated mito-ROS in disease-related proarrhythmic Ca2+ mishandling. These data establish nonlinear mito-[Ca2+]/mito-ROS relationship, whereby partial restoration of mito-[Ca2+] in diseased VMs is protective, whereas further enhancement of MCU-mediated Ca2+ uptake exacerbates damaging mito-ROS emission.NEW & NOTEWORTHY Defective intracellular Ca2+ homeostasis and aberrant mitochondrial function are common features in cardiac disease. Here, we directly compared potential benefits of mito-ROS scavenging and restoration of mito-Ca2+ uptake by overexpressing MCU in ventricular myocytes from hypertrophic rat hearts. Experiments using novel mito-ROS and Ca2+ biosensors demonstrated that mito-ROS scavenging rescued both cytosolic and mito-Ca2+ homeostasis, whereas moderate and high MCU overexpression demonstrated disparate effects on mito-ROS emission, with only a moderate increase in MCU being beneficial.
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MESH Headings
- Adrenergic beta-Agonists/pharmacology
- Animals
- Arrhythmias, Cardiac/genetics
- Arrhythmias, Cardiac/metabolism
- Arrhythmias, Cardiac/pathology
- Arrhythmias, Cardiac/physiopathology
- Biosensing Techniques
- Calcium/metabolism
- Calcium Channels/genetics
- Calcium Channels/metabolism
- Calcium Signaling/drug effects
- Cells, Cultured
- Disease Models, Animal
- Heart Rate
- Hypertrophy, Left Ventricular/genetics
- Hypertrophy, Left Ventricular/metabolism
- Hypertrophy, Left Ventricular/pathology
- Hypertrophy, Left Ventricular/physiopathology
- Male
- Microscopy, Confocal
- Mitochondria, Heart/drug effects
- Mitochondria, Heart/genetics
- Mitochondria, Heart/metabolism
- Mitochondria, Heart/pathology
- Myocardial Contraction
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Rats, Sprague-Dawley
- Reactive Oxygen Species/metabolism
- Up-Regulation
- Ventricular Function, Left
- Ventricular Remodeling
- Rats
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Affiliation(s)
- Shanna Hamilton
- Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio
| | - Radmila Terentyeva
- Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio
| | - Fruzsina Perger
- Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio
| | - Benjamín Hernández Orengo
- Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio
| | - Benjamin Martin
- Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio
| | - Matthew W Gorr
- Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio
- College of Nursing, The Ohio State University, Columbus, Ohio
| | - Andriy E Belevych
- Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio
| | - Richard T Clements
- Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island
| | - Sandor Györke
- Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio
| | - Dmitry Terentyev
- Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio
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37
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Wu Y, Chen L, Wang C. Understanding the molecular role of syndecan-1 in the regulation of caspase-6 during the progression of cardiac arrhythmia. Exp Ther Med 2021; 22:1180. [PMID: 34475970 PMCID: PMC8406766 DOI: 10.3892/etm.2021.10614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 06/24/2021] [Indexed: 12/02/2022] Open
Abstract
The role of caspase-6 in heart disease is not well understood, particularly with respect to cardiac arrhythmia. Also, the function of syndecan-1 in the stimulation of inflammation or a regenerative response after cardiac injury is unclear. Leptin receptor-deficient (C57BL/KS-leprdb/leprdb) mice were used in the present study. In addition to developing type 2 diabetes, they also develop initial- and end-stage cardiac arrhythmia after 5 and 8 months, respectively. The initial and end-stage arrhythmias were confirmed through progressive variations in the PP intervals observable in electrocardiograms. Histopathological images of the cardiac tissue exhibited scattered and loosened cardiac cells at the initial stage of cardiac arrhythmia, whereas tissue hardness and extensive structural changes in cardiomyocytes were evident at the end stage. At the molecular level, the progressive upregulation of caspase-6 was observed as the cardiac arrhythmia progressed. In the initial stage of arrhythmia, immunohistochemistry revealed that caspase-6 was expressed at the surface of cardiac cells, suggesting that caspase-6 targeted the extracellular matrix, leading to a loosening of the cardiac tissue structure. In the end stage of cardiac arrhythmia, caspase-6 expression was abundant in the cytoplasm, as well as at the cell surface, suggesting that caspase-6 may have cleaved intermediate filaments, paving the way for cellular morphological changes and apoptosis. Notably, syndecan-1 was upregulated 5.8-fold in the initial stage of cardiac arrhythmia, but downregulated at the end stage. Syndecan-1 may restrict the expression of caspase-6 in the initial stage of cardiac arrhythmia, while its downregulation at the end stage may allow destructive changes via caspase-6 overexpression. Furthermore, the knockdown of syndecan-1 using small interfering RNA enhanced the expression of caspase-6 in the cardiac tissue by factors of 1.8 and 1.2 at the initial and end stages of cardiac arrhythmia, respectively, compared with that in non-silenced cardiac tissue. Therefore, it may be concluded that syndecan-1 plays a major role in the regulation of caspase-6 during the pathological stages of cardiac arrhythmia.
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Affiliation(s)
- Yuanchu Wu
- Department of Cardiology, Affiliated Wujiang Hospital of Nantong University, Suzhou, Jiangsu 215200, P.R. China
| | - Lin Chen
- Department of Cardiology, Affiliated Wujiang Hospital of Nantong University, Suzhou, Jiangsu 215200, P.R. China
| | - Caihong Wang
- Department of Cardiology, Affiliated Wujiang Hospital of Nantong University, Suzhou, Jiangsu 215200, P.R. China
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Sadredini M, Manotheepan R, Lehnart SE, Anderson ME, Sjaastad I, Stokke MK. The oxidation-resistant CaMKII-MM281/282VV mutation does not prevent arrhythmias in CPVT1. Physiol Rep 2021; 9:e15030. [PMID: 34558218 PMCID: PMC8461029 DOI: 10.14814/phy2.15030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 08/11/2021] [Accepted: 08/16/2021] [Indexed: 11/24/2022] Open
Abstract
Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) is an inherited arrhythmogenic disorder caused by missense mutations in the cardiac ryanodine receptors (RyR2), that result in increased β-adrenoceptor stimulation-induced diastolic Ca2+ leak. We have previously shown that exercise training prevents arrhythmias in CPVT1, potentially by reducing the oxidation of Ca2+ /calmodulin-dependent protein kinase type II (CaMKII). Therefore, we tested whether an oxidation-resistant form of CaMKII protects mice carrying the CPVT1-causative mutation RyR2-R2474S (RyR2-RS) against arrhythmias. Antioxidant treatment (N-acetyl-L-cysteine) reduced the frequency of β-adrenoceptor stimulation-induced arrhythmogenic Ca2+ waves in isolated cardiomyocytes from RyR2-RS mice. To test whether the prevention of CaMKII oxidation exerts an antiarrhythmic effect, mice expressing the oxidation-resistant CaMKII-MM281/282VV variant (MMVV) were crossed with RyR2-RS mice to create a double transgenic model (RyR2-RS/MMVV). Wild-type mice served as controls. Telemetric ECG surveillance revealed an increased incidence of ventricular tachycardia and an increased arrhythmia score in both RyR2-RS and RyR2-RS/MMVV compared to wild-type mice, both following a β-adrenoceptor challenge (isoprenaline i.p.), and following treadmill exercise combined with a β-adrenoceptor challenge. There were no differences in the incidence of arrhythmias between RyR2-RS and RyR2-RS/MMVV mice. Furthermore, no differences were observed in β-adrenoceptor stimulation-induced Ca2+ waves in RyR2-RS/MMVV compared to RyR2-RS. In conclusion, antioxidant treatment reduces β-adrenoceptor stimulation-induced Ca2+ waves in RyR2-RS cardiomyocytes. However, oxidation-resistant CaMKII-MM281/282VV does not protect RyR2-RS mice from β-adrenoceptor stimulation-induced Ca2+ waves or arrhythmias. Hence, alternative oxidation-sensitive targets need to be considered to explain the beneficial effect of antioxidant treatment on Ca2+ waves in cardiomyocytes from RyR2-RS mice.
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Affiliation(s)
- Mani Sadredini
- Institute for Experimental Medical Research and KG Jebsen Cardiac Research CentreOslo University Hospital and University of OsloOsloNorway
| | - Ravinea Manotheepan
- Institute for Experimental Medical Research and KG Jebsen Cardiac Research CentreOslo University Hospital and University of OsloOsloNorway
| | - Stephan E. Lehnart
- Heart Research Center GöttingenDepartment of Cardiology and PulmonologyUniversity Medical Center GöttingenGeorg August University GöttingenGöttingenGermany
- Cluster of Excellence “Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells” (MBExC)University of GöttingenGöttingenGermany
- DZHK (German Centre for Cardiovascular Research)GöttingenGermany
| | - Mark E. Anderson
- Division of CardiologyDepartment of MedicineThe Johns Hopkins University School of MedicineBaltimoreUSA
| | - Ivar Sjaastad
- Institute for Experimental Medical Research and KG Jebsen Cardiac Research CentreOslo University Hospital and University of OsloOsloNorway
| | - Mathis K. Stokke
- Institute for Experimental Medical Research and KG Jebsen Cardiac Research CentreOslo University Hospital and University of OsloOsloNorway
- Department of CardiologyOslo University HospitalRikshospitaletOsloNorway
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Tuleta I, Frangogiannis NG. Fibrosis of the diabetic heart: Clinical significance, molecular mechanisms, and therapeutic opportunities. Adv Drug Deliv Rev 2021; 176:113904. [PMID: 34331987 PMCID: PMC8444077 DOI: 10.1016/j.addr.2021.113904] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 07/19/2021] [Accepted: 07/24/2021] [Indexed: 01/02/2023]
Abstract
In patients with diabetes, myocardial fibrosis may contribute to the pathogenesis of heart failure and arrhythmogenesis, increasing ventricular stiffness and delaying conduction. Diabetic myocardial fibrosis involves effects of hyperglycemia, lipotoxicity and insulin resistance on cardiac fibroblasts, directly resulting in increased matrix secretion, and activation of paracrine signaling in cardiomyocytes, immune and vascular cells, that release fibroblast-activating mediators. Neurohumoral pathways, cytokines, growth factors, oxidative stress, advanced glycation end-products (AGEs), and matricellular proteins have been implicated in diabetic fibrosis; however, the molecular links between the metabolic perturbations and activation of a fibrogenic program remain poorly understood. Although existing therapies using glucose- and lipid-lowering agents and neurohumoral inhibition may act in part by attenuating myocardial collagen deposition, specific therapies targeting the fibrotic response are lacking. This review manuscript discusses the clinical significance, molecular mechanisms and cell biology of diabetic cardiac fibrosis and proposes therapeutic targets that may attenuate the fibrotic response, preventing heart failure progression.
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Affiliation(s)
- Izabela Tuleta
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx NY, USA
| | - Nikolaos G Frangogiannis
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx NY, USA.
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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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Li Y, Huang Y, Cheng X, He Y, Hu X. Whole body hypoxic preconditioning-mediated multiorgan protection in db/db mice via nitric oxide-BDNF-GSK-3β-Nrf2 signaling pathway. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2021; 25:281-296. [PMID: 34187947 PMCID: PMC8255126 DOI: 10.4196/kjpp.2021.25.4.281] [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] [Received: 08/18/2020] [Revised: 09/18/2020] [Accepted: 09/19/2020] [Indexed: 11/15/2022]
Abstract
The beneficial effects of hypoxic preconditioning are abolished in the diabetes. The present study was designed to investigate the protective effects and mechanisms of repeated episodes of whole body hypoxic preconditioning (WBHP) in db/db mice. The protective effects of preconditioning were explored on diabetesinduced vascular dysfunction, cognitive impairment and ischemia-reperfusion (IR)-induced increase in myocardial injury. Sixteen-week old db/db (diabetic) and C57BL/6 (non-diabetic) mice were employed. There was a significant impairment in cognitive function (Morris Water Maze test), endothelial function (acetylcholineinduced relaxation in aortic rings) and a significant increase in IR-induced heart injury (Langendorff apparatus) in db/db mice. WBHP stimulus was given by exposing mice to four alternate cycles of low (8%) and normal air O2 for 10 min each. A single episode of WBHP failed to produce protection; however, two and three episodes of WBHP significantly produced beneficial effects on the heart, brain and blood vessels. There was a significant increase in the levels of brain-derived neurotrophic factor (BDNF) and nitric oxide (NO) in response to 3 episodes of WBHP. Moreover, pretreatment with the BDNF receptor, TrkB antagonist (ANA-12) and NO synthase inhibitor (LNAME) attenuated the protective effects imparted by three episodes of WBHP. These pharmacological agents abolished WBHP-induced restoration of p-GSK-3β/GSK-3β ratio and Nrf2 levels in IR-subjected hearts. It is concluded that repeated episodes of WHBP attenuate cognitive impairment, vascular dysfunction and enhancement in IRinduced myocardial injury in diabetic mice be due to increase in NO and BDNF levels that may eventually activate GSK-3β and Nrf2 signaling pathway to confer protection.
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Affiliation(s)
- Yuefang Li
- Cadre Ward the No.901 Hospital of the Joint Logistics Support Unit of the Chinese People's Liberation Army, Hefei, Anhui 230031, P.R. China
| | - Yan Huang
- Cadre Ward the No.901 Hospital of the Joint Logistics Support Unit of the Chinese People's Liberation Army, Hefei, Anhui 230031, P.R. China
| | - Xi Cheng
- Cadre Ward the No.901 Hospital of the Joint Logistics Support Unit of the Chinese People's Liberation Army, Hefei, Anhui 230031, P.R. China
| | - Youjun He
- Cadre Ward the No.901 Hospital of the Joint Logistics Support Unit of the Chinese People's Liberation Army, Hefei, Anhui 230031, P.R. China
| | - Xin Hu
- Cadre Ward the No.901 Hospital of the Joint Logistics Support Unit of the Chinese People's Liberation Army, Hefei, Anhui 230031, P.R. China
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Hegyi B, Fasoli A, Ko CY, Van BW, Alim CC, Shen EY, Ciccozzi MM, Tapa S, Ripplinger CM, Erickson JR, Bossuyt J, Bers DM. CaMKII Serine 280 O-GlcNAcylation Links Diabetic Hyperglycemia to Proarrhythmia. Circ Res 2021; 129:98-113. [PMID: 33926209 PMCID: PMC8221539 DOI: 10.1161/circresaha.120.318402] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 04/22/2021] [Accepted: 04/28/2021] [Indexed: 12/16/2022]
Abstract
[Figure: see text].
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MESH Headings
- Action Potentials
- Adult
- Aged
- Animals
- Arrhythmias, Cardiac/enzymology
- Arrhythmias, Cardiac/genetics
- Arrhythmias, Cardiac/physiopathology
- Biomarkers/blood
- Blood Glucose/metabolism
- Calcium Signaling
- Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics
- Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism
- Case-Control Studies
- Diabetes Mellitus, Experimental/blood
- Diabetes Mellitus, Experimental/enzymology
- Diabetes Mellitus, Experimental/genetics
- Excitation Contraction Coupling
- Female
- Glycosylation
- Heart Rate
- Humans
- Male
- Mice, Inbred C57BL
- Mice, Inbred ICR
- Mice, Transgenic
- Middle Aged
- Mutation
- Myocardial Contraction
- Myocytes, Cardiac/enzymology
- NADPH Oxidase 2/genetics
- NADPH Oxidase 2/metabolism
- Phosphorylation
- Protein Processing, Post-Translational
- Mice
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Affiliation(s)
- Bence Hegyi
- Department of Pharmacology, University of California, Davis (B.H., A.F., C.Y.K., B.W.V., C.C.A., E.Y.S., M.M.C., S.T., C.M.R., J.B., D.M.B.)
| | - Anna Fasoli
- Department of Pharmacology, University of California, Davis (B.H., A.F., C.Y.K., B.W.V., C.C.A., E.Y.S., M.M.C., S.T., C.M.R., J.B., D.M.B.)
| | - Christopher Y. Ko
- Department of Pharmacology, University of California, Davis (B.H., A.F., C.Y.K., B.W.V., C.C.A., E.Y.S., M.M.C., S.T., C.M.R., J.B., D.M.B.)
| | - Benjamin W. Van
- Department of Pharmacology, University of California, Davis (B.H., A.F., C.Y.K., B.W.V., C.C.A., E.Y.S., M.M.C., S.T., C.M.R., J.B., D.M.B.)
| | - Chidera C. Alim
- Department of Pharmacology, University of California, Davis (B.H., A.F., C.Y.K., B.W.V., C.C.A., E.Y.S., M.M.C., S.T., C.M.R., J.B., D.M.B.)
| | - Erin Y. Shen
- Department of Pharmacology, University of California, Davis (B.H., A.F., C.Y.K., B.W.V., C.C.A., E.Y.S., M.M.C., S.T., C.M.R., J.B., D.M.B.)
| | - Marisa M. Ciccozzi
- Department of Pharmacology, University of California, Davis (B.H., A.F., C.Y.K., B.W.V., C.C.A., E.Y.S., M.M.C., S.T., C.M.R., J.B., D.M.B.)
| | - Srinivas Tapa
- Department of Pharmacology, University of California, Davis (B.H., A.F., C.Y.K., B.W.V., C.C.A., E.Y.S., M.M.C., S.T., C.M.R., J.B., D.M.B.)
| | - Crystal M. Ripplinger
- Department of Pharmacology, University of California, Davis (B.H., A.F., C.Y.K., B.W.V., C.C.A., E.Y.S., M.M.C., S.T., C.M.R., J.B., D.M.B.)
| | - Jeffrey R. Erickson
- Department of Physiology and HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand (J.R.E.)
| | - Julie Bossuyt
- Department of Pharmacology, University of California, Davis (B.H., A.F., C.Y.K., B.W.V., C.C.A., E.Y.S., M.M.C., S.T., C.M.R., J.B., D.M.B.)
| | - Donald M. Bers
- Department of Pharmacology, University of California, Davis (B.H., A.F., C.Y.K., B.W.V., C.C.A., E.Y.S., M.M.C., S.T., C.M.R., J.B., D.M.B.)
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Multi-Organ Protective Effects of Curcumin Nanoparticles on Drug-Induced Acute Myocardial Infarction in Rats with Type 1 Diabetes Mellitus. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app11125497] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The objectives of this study were to investigate the cardio-protective, hepatoprotective and nephroprotective effects of curcumin nanoparticle (NC) pretreatment compared to conventional curcumin (CC) on acute myocardial infarction (AMI) in rats with type 1 diabetes mellitus (T1DM). Fifty-six Wister Bratislava rats were divided into eight groups. The first four groups—C (control group), AMI (group with AMI), T1DM (group with T1DM), and T1DM-AMI (group with T1DM and AMI)—received only saline (S) during the whole experiment. Two groups—S-T1DM-CC-AMI and S-T1DM-NC-AMI—were pretreated with S before T1DM induction. The S-T1DM-CC-AMI group received CC (200 mg/Kg bw (bw—body weight)) after T1DM induction, while the S-T1DM-NC-AMI group received NC (200 mg/Kg bw) after T1DM induction. the CC-T1DM-CC-AMI group received CC (200 mg/Kg bw) during the whole experiment. Similarly, the NC-T1DM-NC-AMI group received NC (200 mg/Kg bw) over the entire experiment. T1DM was induced on day 7 using a single dose of streptozotocin (STZ). AMI was induced with isoproterenol (ISO) on day 22. Both curcumin formulations, CC and NC, prevented the following electrocardiographic changes: prolongation of the QRS complex, enlargement of QT and QTc intervals, and ST-segment elevation. Glucose levels and lipid profile parameters were reduced up to 1.9 times, while C-peptide serum levels were increased up to 1.6 times in groups that received CC or NC. Liver function parameters (aspartate transaminase, alanine transaminase) and kidney function parameters (creatinine, urea) were reduced 4.8 times, and histological changes of liver and kidney tissue were improved by CC or NC administration. Pretreatment with NC proved significantly higher cardioprotective, hepatoprotective and nephroprotective effects in the case of AMI in T1DM.
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Impaired regulation of heart rate and sinoatrial node function by the parasympathetic nervous system in type 2 diabetic mice. Sci Rep 2021; 11:12465. [PMID: 34127743 PMCID: PMC8203800 DOI: 10.1038/s41598-021-91937-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 05/31/2021] [Indexed: 01/01/2023] Open
Abstract
Heart rate (HR) and sinoatrial node (SAN) function are modulated by the autonomic nervous system. HR regulation by the parasympathetic nervous system (PNS) is impaired in diabetes mellitus (DM), which is denoted cardiovascular autonomic neuropathy. Whether blunted PNS effects on HR in type 2 DM are related to impaired responsiveness of the SAN to PNS agonists is unknown. This was investigated in type 2 diabetic db/db mice in vivo and in isolated SAN myocytes. The PNS agonist carbachol (CCh) had a smaller inhibitory effect on HR, while HR recovery time after CCh removal was accelerated in db/db mice. In isolated SAN myocytes CCh reduced spontaneous action potential firing frequency but this effect was reduced in db/db mice due to blunted effects on diastolic depolarization slope and maximum diastolic potential. Impaired effects of CCh occurred due to enhanced desensitization of the acetylcholine-activated K+ current (IKACh) and faster IKACh deactivation. IKACh alterations were reversed by inhibition of regulator of G-protein signaling 4 (RGS4) and by the phospholipid PIP3. SAN expression of RGS4 was increased in db/db mice. Impaired PNS regulation of HR in db/db mice occurs due to reduced responsiveness of SAN myocytes to PNS agonists in association with enhanced RGS4 activity.
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Yang Y, Jiang K, Liu X, Qin M, Xiang Y. CaMKII in Regulation of Cell Death During Myocardial Reperfusion Injury. Front Mol Biosci 2021; 8:668129. [PMID: 34141722 PMCID: PMC8204011 DOI: 10.3389/fmolb.2021.668129] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 05/10/2021] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular disease is the leading cause of death worldwide. In spite of the mature managements of myocardial infarction (MI), post-MI reperfusion (I/R) injury results in high morbidity and mortality. Cardiomyocyte Ca2+ overload is a major factor of I/R injury, initiating a cascade of events contributing to cardiomyocyte death and myocardial dysfunction. Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a critical role in cardiomyocyte death response to I/R injury, whose activation is a key feature of myocardial I/R in causing intracellular mitochondrial swelling, endoplasmic reticulum (ER) Ca2+ leakage, abnormal myofilament contraction, and other adverse reactions. CaMKII is a multifunctional serine/threonine protein kinase, and CaMKIIδ, the dominant subtype in heart, has been widely studied in the activation, location, and related pathways of cardiomyocytes death, which has been considered as a potential targets for pharmacological inhibition. In this review, we summarize a brief overview of CaMKII with various posttranslational modifications and its properties in myocardial I/R injury. We focus on the molecular mechanism of CaMKII involved in regulation of cell death induced by myocardial I/R including necroptosis and pyroptosis of cardiomyocyte. Finally, we highlight that targeting CaMKII modifications and cell death involved pathways may provide new insights to understand the conversion of cardiomyocyte fate in the setting of myocardial I/R injury.
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Affiliation(s)
- Yingjie Yang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Kai Jiang
- Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xu Liu
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Mu Qin
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yaozu Xiang
- Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
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CaMKII oxidation is a critical performance/disease trade-off acquired at the dawn of vertebrate evolution. Nat Commun 2021; 12:3175. [PMID: 34039988 PMCID: PMC8155201 DOI: 10.1038/s41467-021-23549-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 05/04/2021] [Indexed: 12/14/2022] Open
Abstract
Antagonistic pleiotropy is a foundational theory that predicts aging-related diseases are the result of evolved genetic traits conferring advantages early in life. Here we examine CaMKII, a pluripotent signaling molecule that contributes to common aging-related diseases, and find that its activation by reactive oxygen species (ROS) was acquired more than half-a-billion years ago along the vertebrate stem lineage. Functional experiments using genetically engineered mice and flies reveal ancestral vertebrates were poised to benefit from the union of ROS and CaMKII, which conferred physiological advantage by allowing ROS to increase intracellular Ca2+ and activate transcriptional programs important for exercise and immunity. Enhanced sensitivity to the adverse effects of ROS in diseases and aging is thus a trade-off for positive traits that facilitated the early and continued evolutionary success of vertebrates. Natural selection may favor traits underlying aging-related diseases if they benefit the young. Wang et al. find that oxidative activation of CaMKII provides physiological benefits critical to the initial and continued success of vertebrates but at the cost of disease, frailty, and shortened lifespan.
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47
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Lang D, Glukhov AV. Cellular and Molecular Mechanisms of Functional Hierarchy of Pacemaker Clusters in the Sinoatrial Node: New Insights into Sick Sinus Syndrome. J Cardiovasc Dev Dis 2021; 8:jcdd8040043. [PMID: 33924321 PMCID: PMC8069964 DOI: 10.3390/jcdd8040043] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/07/2021] [Accepted: 04/08/2021] [Indexed: 12/17/2022] Open
Abstract
The sinoatrial node (SAN), the primary pacemaker of the heart, consists of a heterogeneous population of specialized cardiac myocytes that can spontaneously produce action potentials, generating the rhythm of the heart and coordinating heart contractions. Spontaneous beating can be observed from very early embryonic stage and under a series of genetic programing, the complex heterogeneous SAN cells are formed with specific biomarker proteins and generate robust automaticity. The SAN is capable to adjust its pacemaking rate in response to environmental and autonomic changes to regulate the heart's performance and maintain physiological needs of the body. Importantly, the origin of the action potential in the SAN is not static, but rather dynamically changes according to the prevailing conditions. Changes in the heart rate are associated with a shift of the leading pacemaker location within the SAN and accompanied by alterations in P wave morphology and PQ interval on ECG. Pacemaker shift occurs in response to different interventions: neurohormonal modulation, cardiac glycosides, pharmacological agents, mechanical stretch, a change in temperature, and a change in extracellular electrolyte concentrations. It was linked with the presence of distinct anatomically and functionally defined intranodal pacemaker clusters that are responsible for the generation of the heart rhythm at different rates. Recent studies indicate that on the cellular level, different pacemaker clusters rely on a complex interplay between the calcium (referred to local subsarcolemmal Ca2+ releases generated by the sarcoplasmic reticulum via ryanodine receptors) and voltage (referred to sarcolemmal electrogenic proteins) components of so-called "coupled clock pacemaker system" that is used to describe a complex mechanism of SAN pacemaking. In this review, we examine the structural, functional, and molecular evidence for hierarchical pacemaker clustering within the SAN. We also demonstrate the unique molecular signatures of intranodal pacemaker clusters, highlighting their importance for physiological rhythm regulation as well as their role in the development of SAN dysfunction, also known as sick sinus syndrome.
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Andreadou I, Daiber A, Baxter GF, Brizzi MF, Di Lisa F, Kaludercic N, Lazou A, Varga ZV, Zuurbier CJ, Schulz R, Ferdinandy P. Influence of cardiometabolic comorbidities on myocardial function, infarction, and cardioprotection: Role of cardiac redox signaling. Free Radic Biol Med 2021; 166:33-52. [PMID: 33588049 DOI: 10.1016/j.freeradbiomed.2021.02.012] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/03/2021] [Accepted: 02/06/2021] [Indexed: 02/06/2023]
Abstract
The morbidity and mortality from cardiovascular diseases (CVD) remain high. Metabolic diseases such as obesity, hyperlipidemia, diabetes mellitus (DM), non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) as well as hypertension are the most common comorbidities in patients with CVD. These comorbidities result in increased myocardial oxidative stress, mainly from increased activity of nicotinamide adenine dinucleotide phosphate oxidases, uncoupled endothelial nitric oxide synthase, mitochondria as well as downregulation of antioxidant defense systems. Oxidative and nitrosative stress play an important role in ischemia/reperfusion injury and may account for increased susceptibility of the myocardium to infarction and myocardial dysfunction in the presence of the comorbidities. Thus, while early reperfusion represents the most favorable therapeutic strategy to prevent ischemia/reperfusion injury, redox therapeutic strategies may provide additive benefits, especially in patients with heart failure. While oxidative and nitrosative stress are harmful, controlled release of reactive oxygen species is however important for cardioprotective signaling. In this review we summarize the current data on the effect of hypertension and major cardiometabolic comorbidities such as obesity, hyperlipidemia, DM, NAFLD/NASH on cardiac redox homeostasis as well as on ischemia/reperfusion injury and cardioprotection. We also review and discuss the therapeutic interventions that may restore the redox imbalance in the diseased myocardium in the presence of these comorbidities.
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Affiliation(s)
- Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece.
| | - Andreas Daiber
- Department of Cardiology 1, Molecular Cardiology, University Medical Center, Langenbeckstr. 1, 55131, Mainz, Germany; Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Langenbeckstr, Germany.
| | - Gary F Baxter
- Division of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, United Kingdom
| | | | - Fabio Di Lisa
- Department of Biomedical Sciences, University of Padova, Italy; Neuroscience Institute, National Research Council of Italy (CNR), Padova, Italy
| | - Nina Kaludercic
- Neuroscience Institute, National Research Council of Italy (CNR), Padova, Italy
| | - Antigone Lazou
- Laboratory of Animal Physiology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece
| | - Zoltán V Varga
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, Hungary
| | - Coert J Zuurbier
- Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Rainer Schulz
- Institute of Physiology, Justus Liebig University Giessen, Giessen, Germany.
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; Pharmahungary Group, Szeged, Hungary
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Involvement of amylin B-H2S-connexin 43 signaling pathway in vascular dysfunction and enhanced ischemia-reperfusion-induced myocardial injury in diabetic rats. Biosci Rep 2021; 40:224904. [PMID: 32436936 PMCID: PMC7280474 DOI: 10.1042/bsr20194154] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 04/24/2020] [Accepted: 04/29/2020] [Indexed: 11/17/2022] Open
Abstract
The present study was designed to investigate the role of amylin, H2S, and connexin 43 in vascular dysfunction and enhanced ischemia–reperfusion (I/R)-induced myocardial injury in diabetic rats. A single dose of streptozotocin (65 mg/kg) was employed to induce diabetes mellitus. After 8 weeks, there was a significant decrease in the plasma levels of amylin, an increase in I/R injury to isolated hearts (increase in CK-MB and cardiac troponin release) on the Langendorff apparatus. Moreover, there was a significant impairment in vascular endothelium function as assessed by quantifying acetylcholine-induced relaxation in norepinephrine-precontracted mesenteric arteries. There was also a marked decrease in the expression of H2S and connexin 43 in the hearts following I/R injury in diabetic rats. Treatment with amylin agonist, pramlintide (100 and 200 µg/kg), and H2S donor, NaHS (10 and 20 μmol/kg) for 2 weeks improved the vascular endothelium function, abolished enhanced myocardial injury and restored the levels of H2S along with connexin 43 in diabetic animals. However, pramlintide and NaHS failed to produce these effects the presence of gap junction blocker, carbenoxolone (20 and 40 mg/kg). Carbenoxolone also abolished the myocardial levels of connexin 43 without affecting the plasma levels of amylin and myocardial levels of H2S. The decrease in the amylin levels with a consequent reduction in H2S and connexin 43 may contribute to inducing vascular dysfunction and enhancing I/R-induced myocardial injury in diabetic rats.
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Meng K, Cai H, Cai S, Hong Y, Zhang X. Adiponectin Modified BMSCs Alleviate Heart Fibrosis via Inhibition TGF-beta1/Smad in Diabetic Rats. Front Cell Dev Biol 2021; 9:644160. [PMID: 33829019 PMCID: PMC8019808 DOI: 10.3389/fcell.2021.644160] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 02/28/2021] [Indexed: 12/22/2022] Open
Abstract
Background: Accumulating evidence suggested that bone marrow mesenchymal stem cells (BMSCs) have therapeutic potential for diabetes and heart diseases. However, the effects of BMSC on reducing myocardial fibrosis need to be optimized. This study aimed to investigate the mechanism of adiponectin (APN) modified BMSCs on myocardial fibrosis in diabetic model in vivo and in vitro. Methods: The high-fat diet combined with streptozotocin (STZ) injection were used to induced diabetic rat model. H9c2 cells were cultured under a high glucose medium as in vitro model. The BMSCs were modified by APN plasmid or APN small interfering RNA (siRNA), then transplanted to the diabetic rats by a single tail-vein injection, or co-cultured with H9c2 cells. Results: We demonstrated that diabetic rats showed typical diabetic symptoms, such as decreased cardiac function, accumulation of pathological lesions and collagen expression. However, these impairments were significantly prevented by the APN modified BMSCs treatment while no effects on APN siRNA modified BMSCs treated diabetic rats. Moreover, we confirmed that APN modified BMSCs could attenuate the expression of TGF-beta1/smad to suppress the myocardial fibrosis in the diabetic rats and high glucose induced H9c2 cells. Conclusion: The present results for the first time showed that APN modified BMSCs exerted protection on cardiac fibrosis via inhibiting TGF-beta1/smad signal pathway in diabetic rats. Our findings suggested that APN modified BMSCs might be a novel and optimal therapy for the diabetic cardiomyopathy in future.
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Affiliation(s)
- Ke Meng
- Department of Anatomy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Emergency Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Huabo Cai
- Department of Emergency Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Simin Cai
- Department of Anatomy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Emergency Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yucai Hong
- Department of Emergency Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoming Zhang
- Department of Anatomy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Emergency Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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