Caveolin-3 and Caveolae regulate ventricular repolarization. (April 2023)

• Record Type: Journal Article
• Authors: Markandeya, Yogananda S.; Gregorich, Zachery R.; Feng, Li; Ramchandran, Vignesh; O' Hara, Thomas; Vaidyanathan, Ravi; Mansfield, Catherine; Keefe, Alexis M.; Beglinger, Carl J.; Best, Jabe M.; Kalscheur, Matthew M.; Lea, Martin R.; Hacker, Timothy A.; Gorelik, Julia; Trayanova, Natalia A.; Eckhardt, Lee L.; Makielski, Jonathan C.; Balijepalli, Ravi C.; Kamp, Timothy J.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 177(2023)
• Page Start: 38
• Page End: 49
• Publication Date: 2023-04
• Subjects: Caveolae -- Arrhythmia -- Ion channels -- Cardiac repolarization -- Action potential; APD Action potential duration -- Cav-3 Caveolin-3 -- Cav-3KO Cardiac-specific, conditional Caveolin-3 knockout mice -- Cav-3Het Cardiac-specific, conditional Caveolin-3 heterozygous knockout mice -- MDP Maximum diastolic potential -- RMP Resting membrane potential; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2023.02.005
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: 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 QTc 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 (Ito, Iss ) and changes in inward currents including slowed inactivation of ICa, L and increased INa, 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. Graphical abstract: Unlabelled Image Highlights: Cav3 knockout in adult mouse heart does not impact basal contractile function. Cardiac-specific knockout of Cav3 greatly reduces caveolae in cardiomyocytes. Loss of Cav-3 delays repolarization in mice by affecting multiple ionic currents. Cav3 knockout in mouse heart increases susceptibility to ventricular arrhythmia. Knockdown of Cav-3 also delays repolarization in human iPSC-cardiomyocytes.