Up-regulation of junctophilin-2 prevents ER stress and apoptosis in hypoxia/reoxygenation-stimulated H9c2 cells

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.

Name thesis:degree_name

M Sc

Discipline thesis:degree_discipline

Pathology

Grantor dc:publisher

The University of Western Ontario

Year dc:date.issued

2017

Author dc:creator

• Su, Zijun

Advisors dc:contributor.advisor

• Dr.Tianqing Peng
• Dr.Stephen Sims

• Cardiomyocytes
• Junctophilin-2
• RyR2
• Calcium
• Calpain
• ER stress
• JNK1/2
• Apoptosis
• hypoxia/re-oxygenation

Language dc:language.iso

en_ca

Handle dc:identifier.uri

https://hdl.handle.net/20.500.14721/34533

OAI identifier oai:identifier

oai:uwo.scholaris.ca:20.500.14721/34533