Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pharmacology and Toxicology

Supervisor

Dr. Peter Chidiac

2nd Supervisor

Dr. Qingping Feng

Co-Supervisor

Abstract

Pathological left ventricular hypertrophy is a maladaptive cardiomyocyte growth response to various cardiovascular conditions such as hypertension, and is a major risk factor for heart failure and stroke. The majority of drugs used to treat cardiovascular diseases target G protein coupled receptors (GPCRs), which are regulated by regulator of G protein signalling (RGS) proteins. RGS2 is a GTPase activating protein which limits Gq- and Gs-mediated signalling, which are known to play major roles in the development of pathological cardiac hypertrophy. In addition to its G protein effects, we have previously shown that RGS2 can also inhibit protein synthesis and cultured cardiomyocyte growth via a region in its RGS domain, RGS2eb, which inhibits the rate-limiting eIF2B/eIF2 step of protein synthesis initiation. Thus, we hypothesized that the in vivo expression of RGS2eb could limit the development of experimentally induced hypertrophy. Herein, we demonstrate that the in vivo cardiomyocyte specific overexpression of RGS2eb prevents the development of cardiac hypertrophy in a transverse aortic constriction (TAC) model of experimental pressure overload, as well as functional loss and the expression of “fetal” genes associated with hypertrophy and heart failure. Although we further hypothesized that the expression of RGS2eb in Rgs2-­/-mice (which are highly sensitive to hypertrophy and heart failure following pressure overload) could compensate for the loss of endogenous RGS2, we were limited in our characterizations by poor survival rates in Rgs2-/-animals following TAC surgery.

Cardiovascular dysfunction is also known to be directly influenced by obesity and weight gain, which reflects the importance of understanding the mechanisms behind metabolic dysregulation. We have previously demonstrated that Rgs2-/- mice exhibit a lean phenotype on a normal chow diet, but still gain weight on a high fat diet. We thus sought to further characterize the metabolic role of RGS2 via Comprehensive Lab Animal Monitoring System (CLAMS) metabolic cages and gene expression analysis of skeletal rather than adipose tissue. Here we report that loss of RGS2 leads to greater use of carbohydrates and significant increases in basal metabolism, as well as increases in associated metabolism-related genes. Altogether, these studies provide new insights into the role of RGS2 in cardiovascular health and metabolism.

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