Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Physiology

Supervisor

Dr Qingping Feng

Abstract

Myocardial infarction (MI) occurs due to the complete occlusion of a coronary artery and is a leading cause of death, and a huge social and economic burden worldwide. Despite advances in treatment, patients still have a poor prognosis and there is a pressing need for strategies to improve cardiac repair post-MI. Stem cell factor (SCF), expressed by many cells and tissues including the myocardium, binds to its receptor, c-kit, and regulates the activity of c-kit-expressing cells. SCF has two isoforms: a soluble (S-SCF), and a membrane-associated isoform (M-SCF). M-SCF is more potent in supporting cell adhesion and survival. To date, little is known about the role of M-SCF in MI. This thesis investigated how M-SCF affects cardiac repair post-MI and the related mechanisms. To study the effects of M-SCF in cardiac repair post-MI, we generated a novel mouse model of inducible cardiac specific over-expression of membrane-associated human SCF (hSCF). I utilized mouse models of MI and ischemia/reperfusion (I/R) induced through permanent and reversible ligation of the left coronary artery, respectively. Using these models, I investigated the effects of hSCF on cardiac function, cardiac repair, and related cellular and molecular mechanisms. I demonstrated for the first time that cardiomyocyte-specific overexpression of hSCF improves myocardial function and animal survival post-MI. These beneficial effects appear to have resulted from increases in c-kit+stem cell retention, neovascularization, and decreases in myocardial apoptosis and cardiac remodeling. I also examined the cardioprotective effects of M-SCF in acute myocardial I/R injury. Overexpression of hSCF decreased myocardial apoptosis and infarct size via Akt-dependent signaling. Furthermore, I found that hSCF overexpression increases CD45-/c-kit+ cell activation following acute I/R through SCF/c-kit signaling. Finally, I examined the role of M-SCF in epicardial activation post-MI. I found that overexpression of hSCF increased epicardial activation, enhanced epicardium-derived cell (EPDC) proliferation and migration via SCF/c-kit signaling, and promoted arteriogenesis post-MI. In conclusion, M-SCF improves cardiac repair and function through inhibiting myocardial apoptosis and cardiac remodeling, and by promoting neovascularization via c-kit+stem cell recruitment and EPDC activation and migration.

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