Heart failure after myocardial infarction (MI) is a significant cause of morbidity/mortality. During MI, cardiomyocyte (CM) death triggers expansion of monocytes and macrophages that clear dying myocardial tissue. Prompt phagocytic clearance of dying cells (efferocytosis) triggers homeostatic tissue remodeling via inducing anti-inflammatory and pro-reparative signaling within the phagocyte, while inefficient clearance, according to our recently published study, leads to delay of inflammation resolution and tissue repair after MI. What remains unclear is the mechanism of CM clearance, including molecular factors that drive interactions between CMs and phagocytes and their physiological significance. My preliminary data suggest that CMs are resistant to efferocytosis and express heightened levels of anti-phagocytic ligand CD47. I also showed that CM efferocytosis efficiency can be increased after blocking CM CD47. The goal of my study is to test the physiologic role of CD47 during post MI inflammation resolution and repair, as well as the mechanism of the anti-phagocytic effect of CD47 on dying CM clearance. I hypothesize that elevated CD47 on apoptotic CMs suppresses efficient efferocytosis by macrophages and in turn, delays myocardial inflammation resolution and accelerates progression to post MI heart failure. Aim I: To determine if acute blockade of CD47 signaling post MI affects CM efferocytosis, inflammation resolution, and cardiac repair in vivo; In a murine cardiac ischemia/reperfusion model, I will administer CD47 blocking antibody to test if blockade CD47 mediated CM/phagocytes interaction could reduce infarct expansion, cardiac function, efferocytosis and inflammation resolution in the heart. Aim II: To determine the molecular mechanism attributed to the inhibitory effect of CD47 on CM efferocytosis. I will look particularly at how caveolin-3 regulates CD47 cell surface presentation during CM death. I will use co-immunoprecipitation and proximity ligation assay to study CD47 and caveolin interaction. The requirement of caveolin-3 on CD47 regulation will be studied in caveolin-3 knockout mice. The results of these studies will elucidate regulators of CD47 that affect CM presentation to phagocytes and potentially reveal novel strategies for helping cardiac repair.
|Effective start/end date||7/1/15 → 6/30/17|
- American Heart Association Midwest Affiliate (15PRE24470119)