Caveolin-3 and Caveolae regulate ventricular repolarization.

Autor: Markandeya YS; Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin Madison, WI, USA; National Institute of Mental Health and Neuroscience, Bengaluru, India., Gregorich ZR; Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin Madison, WI, USA., Feng L; Department of Cardiology, Beijing Anzhen Hospital, Captial Medical University, National Clinical Research Center for Cardiovascular Diseases, Beijing, China., Ramchandran V; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA., O' Hara T; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA., Vaidyanathan R; Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin Madison, WI, USA., Mansfield C; National Heart and Lung Institute, Imperial College London, ICTEM, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK., Keefe AM; Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin Madison, WI, USA., Beglinger CJ; Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin Madison, WI, USA., Best JM; Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin Madison, WI, USA., Kalscheur MM; Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin Madison, WI, USA., Lea MR; Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin Madison, WI, USA., Hacker TA; Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin Madison, WI, USA., Gorelik J; National Heart and Lung Institute, Imperial College London, ICTEM, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK., Trayanova NA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA., Eckhardt LL; Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin Madison, WI, USA., Makielski JC; Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin Madison, WI, USA., Balijepalli RC; Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin Madison, WI, USA., Kamp TJ; Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin Madison, WI, USA. Electronic address: tjk@medicine.wisc.edu.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2023 Apr; Vol. 177, pp. 38-49. Date of Electronic Publication: 2023 Feb 24.
DOI: 10.1016/j.yjmcc.2023.02.005
Abstrakt: Rationale: Flask-shaped invaginations of the cardiomyocyte sarcolemma called caveolae require the structural protein caveolin-3 (Cav-3) and host a variety of ion channels, transporters, and signaling molecules. Reduced Cav-3 expression has been reported in models of heart failure, and variants in CAV3 have been associated with the inherited long-QT arrhythmia syndrome. Yet, it remains unclear whether alterations in Cav-3 levels alone are sufficient to drive aberrant repolarization and increased arrhythmia risk.
Objective: To determine the impact of cardiac-specific Cav-3 ablation on the electrophysiological properties of the adult mouse heart.
Methods and Results: Cardiac-specific, inducible Cav3 homozygous knockout (Cav-3KO) mice demonstrated a marked reduction in Cav-3 expression by Western blot and loss of caveolae by electron microscopy. However, there was no change in macroscopic cardiac structure or contractile function. The QT c interval was increased in Cav-3KO mice, and there was an increased propensity for ventricular arrhythmias. Ventricular myocytes isolated from Cav-3KO mice exhibited a prolonged action potential duration (APD) that was due to reductions in outward potassium currents (I to , I ss ) and changes in inward currents including slowed inactivation of I Ca,L and increased I Na,L . Mathematical modeling demonstrated that the changes in the studied ionic currents were adequate to explain the prolongation of the mouse ventricular action potential. Results from human iPSC-derived cardiomyocytes showed that shRNA knockdown of Cav-3 similarly prolonged APD.
Conclusion: We demonstrate that Cav-3 and caveolae regulate cardiac repolarization and arrhythmia risk via the integrated modulation of multiple ionic currents.
Competing Interests: Declaration of Competing Interest TJK is a consultant for Fujifilm Cellular Dynamics Incorporated.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: