University of Western Ontario - Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Physiology

Supervisor

Dr. Qingping Feng

Abstract

Tumor necrosis factor-a (TNF-alpha) is a pro-inflammatory cytokine and its high levels of expression in the heart leads to cardiac dysfunction in sepsis. However, the underlying molecular mechanisms of regulating myocardial TNF-alpha expression are not fully understood. The aim of this thesis was to investigate the role of Rac1 in myocardial TNF-alpha expression and cardiac dysfunction during sepsis. Studies were performed using cultured neonatal cardiomyocytes and a mouse model of endotoxemia.

PI3K-mediated Rac1 activation is required for induction of TNF-alpha mRNA and protein expression in cardiomyocytes and cardiac dysfunction during endotoxemia. Rac1 promotes TNF-alpha mRNA expression via NADPH oxidase/ERK1/2 and PAK1/p38 pathways. Rac1-mediated NADPH oxidase activation enhances TNF-alpha protein production via Na/K-ATPase inhibition and Ca2+/CaMK-dependent mTOR activation. On the other hand, Rac1/PAK1 pathway induces myocardial MKP-1 expression via JNK1. MKP-1 attenuates ERK1/2 and p38 activation, thus limiting myocardial TNF-alpha expression and improving cardiac function in endotoxemia. These findings provide novel insight into the signal transduction mechanisms that regulate myocardial TNF-alpha expression, and may have therapeutic implications in the treatment of sepsis.