Up-regulation of junctophilin-2 prevents ER stress and apoptosis in hypoxia/reoxygenation-stimulated H9c2 cells
type: CreativeWork
description: Ischemic heart disease is the leading cause of death, and reperfusion which can restore blood flow is the primary therapy. However, reperfusion can induce further damage to cardiomyocytes, a condition described as ischemia-reperfusion (I/R) injury. I/R is now recognized as a combination determining the final myocardial infarction size. Although the mechanisms underlying I/R-induced cardiac injury remain incompletely understood, emerging evidence suggests that intracellular Ca2+ mishandling during I/R plays a key role in cell death. Junctophilin-2 (JPH2) is a junctional membrane-binding structural protein. It mechanically maintains the fixed distance between the T-tubule and the sarcoplasmic reticulum (SR), thus allowing the proper Ca2+-induced Ca2+ release for stable excitation-contraction coupling. Down-regulation of JPH2 has been observed in diseased hearts and is related to cardiac dysfunction and T-tubule remodeling. In this study, we show that the protein levels of JPH2 are down-regulated in cardiomyocytes following hypoxia/re-oxygenation (H/R), a condition simulating I/R. Up-regulation of JPH2 protects cardiomyocytes against H/R-induced apoptotic cell death. Furthermore, we reveal that up-regulation of JPH2 reduces ryanodine receptor-2 (RyR2)-mediated SR Ca2+ leak and inhibits calcium-dependent calpain activation in H/R-stimulated cardiomyocytes. Lastly, up-regulation of JPH2 prevents endoplasmic reticulum stress in response to H/R. In summary, we demonstrate for the first time that JPH2 prevents H/R-induced apoptosis by blocking Ca2+ leakage via RyR2 in cardiomyocytes. Thus, up-regulating JPH2 may represent a new therapeutic strategy to treat ischemic heart disease.
abstract: Ischemic heart disease is the leading cause of death, and reperfusion which can restore blood flow is the primary therapy. However, reperfusion can induce further damage to cardiomyocytes, a condition described as ischemia-reperfusion (I/R) injury. I/R is now recognized as a combination determining the final myocardial infarction size. Although the mechanisms underlying I/R-induced cardiac injury remain incompletely understood, emerging evidence suggests that intracellular Ca2+ mishandling during I/R plays a key role in cell death. Junctophilin-2 (JPH2) is a junctional membrane-binding structural protein. It mechanically maintains the fixed distance between the T-tubule and the sarcoplasmic reticulum (SR), thus allowing the proper Ca2+-induced Ca2+ release for stable excitation-contraction coupling. Down-regulation of JPH2 has been observed in diseased hearts and is related to cardiac dysfunction and T-tubule remodeling. In this study, we show that the protein levels of JPH2 are down-regulated in cardiomyocytes following hypoxia/re-oxygenation (H/R), a condition simulating I/R. Up-regulation of JPH2 protects cardiomyocytes against H/R-induced apoptotic cell death. Furthermore, we reveal that up-regulation of JPH2 reduces ryanodine receptor-2 (RyR2)-mediated SR Ca2+ leak and inhibits calcium-dependent calpain activation in H/R-stimulated cardiomyocytes. Lastly, up-regulation of JPH2 prevents endoplasmic reticulum stress in response to H/R. In summary, we demonstrate for the first time that JPH2 prevents H/R-induced apoptosis by blocking Ca2+ leakage via RyR2 in cardiomyocytes. Thus, up-regulating JPH2 may represent a new therapeutic strategy to treat ischemic heart disease.
author: Su, Zijun
language: en_ca
keywords: Cardiomyocytes, Junctophilin-2, RyR2, Calcium, Calpain, ER stress, JNK1/2, Apoptosis, hypoxia/re-oxygenation
date published: 2017-02-15
date modified: 2026-07-27T21:55:54Z
provider: Western University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: The University of Western Ontario

PropertyValue
property ID: Handle
value: https://hdl.handle.net/20.500.14721/34533