Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Pathology

Supervisor

Peng, Tianqing

2nd Supervisor

Jones, Douglas

Co-Supervisor

Abstract

Cardiac lipotoxicity may induce cardiomyocyte apoptosis, eventually leading to myocardial dysfunction and heart failure. This study investigated whether and how junctophilin-2 (JPH2) plays a role in palmitate-induced apoptosis in cardiomyocytes. Here, we found palmitate incubation reduced JPH2 protein levels, increased cytosolic Ca2+ and induced apoptosis in cardiomyocytes. JPH2 over-expression prevented the increased cytosolic Ca2+ and apoptosis in palmitate-stimulated cardiomyocytes. JPH2 over-expression also attenuated palmitate-induced CCAAT-enhancer-binding protein homologous protein (CHOP) expression and CHOP deletion alleviated palmitate-induced apoptosis. Furthermore, blocking Ca2+ release from ryanodine receptor-2 (RyR2) prevented palmitate-stimulated CHOP induction and apoptosis. Additionally, JPH2 silencing elevated cytosolic Ca2+, induced CHOP expression and apoptosis in cardiomyocytes; these effects of JPH2 silencing were inhibited by blocking Ca2+ release from RyR2. In summary, we demonstrate that JPH2 attenuates palmitate-induced apoptosis by reducing Ca2+ release from RyR2 and preventing CHOP expression in cardiomyocytes. Thus, targeting JPH2 may represent a new therapeutic strategy to treat cardiac lipotoxicity.

Summary for Lay Audience

The heart has both the greatest caloric needs and the most robust consumption of fatty acids of the human organs. Under certain abnormal or disease conditions, heart muscle cells get more fatty acids than they need and thus, the heart accumulates lipids. Excess lipids can directly damage heart muscle cell structures, resulting in the heart not working properly, a condition described as "cardiac lipotoxicity". Two human metabolic disorders are caused by excess lipid accumulation in heart muscle cells: obesity-related heart muscle disease in association with sudden heart death, and diabetic heart disease. The outcomes of cardiac lipotoxicity include severe heart impairment leading to death or needing replacement of the heart. Since type-2 diabetes and obesity are very common, cardiac lipotoxicity represents a major public health concern. However, effective treatments are limited for patients, which represents a major gap in patient care. Thus, further researches are urgently needed to better understand this disease, identify new targets for treatment and develop effective treatment modalities.

The objective of this study was to understand how a protein called "junctophilin-2" is involved in cardiac lipotoxicity. Since the levels of this junctophilin-2 protein are reduced in heart muscle cells during lipotoxicity, we examined whether addition of junctophilin-2 reduces heart muscle cell death caused by palmitate, a toxic lipid that has been widely applied in the study of cardiac lipotoxicity. It is well known that junctophilin-2 is important in maintaining a structure within cells which delivers ions (e.g. calcium) signals to force-generating fibers in heart muscle cells, leading to contraction. We examined how junctophilin-2 normalizes calcium signals and inhibits the occurrence of a condition called "endoplasmic reticulum stress", which causes heart muscle cell death under over-supply of palmitate. Thus, this study will identify new targets for treatment.

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