SERCA2a ameliorates cardiomyocyte T-tubule remodeling via the calpain/JPH2 pathway to improve cardiac function in myocardial ischemia/reperfusion mice

Shuai Wang,You Zhou,Dongye Li,Jingwen Chen,Chaofan Wang,Yuanyuan Luo,Rongsheng Kan,Haochen Xuan,Tongda Xu,Junhong Chen

doi:10.1038/s41598-021-81570-4

Shuai Wang, You Zhou + Show 8 more

Open Access

https://doi.org/10.1038/s41598-021-81570-4

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Journal: Scientific Reports	Publication Date: Jan 21, 2021
Citations: 13	License type: open-access

Affiliation: Xuzhou Medical College

Abstract

Transverse-tubules (T-tubules) play pivotal roles in Ca2+-induced, Ca2+ release and excitation–contraction coupling in cardiomyocytes. The purpose of this study was to uncover mechanisms where sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2a) improved cardiac function through T-tubule regulation during myocardial ischemia/reperfusion (I/R). SERCA2a protein expression, cytoplasmic [Ca2+]i, calpain activity, junctophilin-2 (JPH2) protein expression and intracellular localization, cardiomyocyte T-tubules, contractility and calcium transients in single cardiomyocytes and in vivo cardiac functions were all examined after SERCA2a knockout and overexpression, and Calpain inhibitor PD150606 (PD) pretreatment, following myocardial I/R. This comprehensive approach was adopted to clarify SERCA2a mechanisms in improving cardiac function in mice. Calpain was activated during myocardial I/R, and led to the proteolytic cleavage of JPH2. This altered the T-tubule network, the contraction function/calcium transients in cardiomyocytes and in vivo cardiac functions. During myocardial I/R, PD pretreatment upregulated JPH2 expression and restored it to its intracellular location, repaired the T-tubule network, and contraction function/calcium transients of cardiomyocytes and cardiac functions in vivo. SERCA2a suppressed calpain activity via [Ca2+]i, and ameliorated these key indices. Our results suggest that SERCA2a ameliorates cardiomyocyte T-tubule remodeling via the calpain/JPH2 pathway, thereby improving cardiac function in myocardial I/R mice.

Highlights

Transverse-tubules (T-tubules) play pivotal roles in Ca2+-induced, Ca2+ release and excitation– contraction coupling in cardiomyocytes
As shown (Fig. 1A), the ST segment was at baseline before myocardial ischemia, and was significantly elevated after myocardial ischemia, falling back to baseline after myocardial reperfusion
Protein expression of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2a) and its mRNA were significantly upregulated in myocardial tissue when transfected by the SERCA2a overexpression adenovirus

Summary

Introduction

Transverse-tubules (T-tubules) play pivotal roles in Ca2+-induced, Ca2+ release and excitation– contraction coupling in cardiomyocytes. SERCA2a protein expression, cytoplasmic [Ca2+]i, calpain activity, junctophilin-2 (JPH2) protein expression and intracellular localization, cardiomyocyte T-tubules, contractility and calcium transients in single cardiomyocytes and in vivo cardiac functions were all examined after SERCA2a knockout and overexpression, and Calpain inhibitor PD150606 (PD) pretreatment, following myocardial I/R. This comprehensive approach was adopted to clarify SERCA2a mechanisms in improving cardiac function in mice. Calpain was activated during myocardial I/R, and led to the proteolytic cleavage of JPH2 This altered the T-tubule network, the contraction function/calcium transients in cardiomyocytes and in vivo cardiac functions. The exact mechanism of SERCA2a regulation of T-tubule remodeling is unclear

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