Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Feng, Qingping

2nd Supervisor

Chidiac, Peter

Co-Supervisor

Abstract

In sepsis, lipopolysaccharide (LPS) activates toll-like receptor 4 to stimulate the release of inflammatory cytokines (e.g. tumor necrosis factor-alpha, TNF-α), leading to cardiac dysfunction. Regulator of G protein signaling 2 (RGS2) limits G protein-coupled receptor signaling by increasing the rate of G protein deactivation or inhibiting G protein-effector interactions. We hypothesized that RGS2 deficiency would enhance proinflammatory responses in endotoxemia. Adult wild-type and RGS2-/- C57BL/6 mice and neonatal cardiomyocytes were treated with LPS and assessed for inflammatory responses and cardiac function. Myocardial TNF-α expression was higher in RGS2-/- mice during endotoxemia. Additionally, cardiac function was impaired in RGS2-/- mice. Phosphorylated p38 levels were higher in the RGS2-/- myocardium in endotoxemia. In vitro, TNF-expression was higher in RGS2-/- cardiomyocytes after LPS stimulation. Our study suggests that RGS2 is cardioprotective and inhibits proinflammatory signaling via p38 in sepsis. Thus, this study suggests a novel therapeutic target for the clinical treatment of sepsis.

Summary for Lay Audience

Sepsis is a major cause of death globally and of in-hospital mortality in Canada. It is caused by an improper response to infection, resulting in inflammation and organ failure. However, there are no drugs specifically targeted for sepsis. The bacterial component, lipopolysaccharide (LPS), causes sepsis by stimulating a proinflammatory response, leading to heart dysfunction and patient death. G protein-coupled receptors (GPCRs) are a family of receptors found in many tissues that regulate a variety of cellular processes. GPCR activities can be limited by regulator of G protein signaling 2 (RGS2). While both RGS2 regulated GPCR signaling and LPS induced inflammatory pathway are well established, how the two signaling pathways interact is not known. The aim of this thesis was to determine the role of RGS2 in LPS induced inflammation in the heart, and identify factors modulated by RGS2. Adult wild-type and RGS2 deficient mice were challenged with LPS, while newborn mouse cardiac cells were isolated and treated with LPS. They were then assessed for inflammatory responses by measuring the levels of TNF-α, a proinflammatory factor. Results show that TNF-α expression was induced by LPS in wild-type mice, and the response was further enhanced in the heart of RGS2 deficient mice. Similarly, LPS-induced TNF-α expression was higher in RGS2 deficient cardiomyocytes. Furthermore, LPS-induced activity of p38, an inflammatory mediator, was also higher in the heart of RGS2 deficient mice. Notably, heart dysfunction was worse in RGS2 deficient mice in sepsis. In conclusion, RGS2 is protective and can inhibit the proinflammatory response in sepsis. This thesis may open up new strategies in the design of drugs for the treatment of sepsis.

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