Fellowship for Manning: Protection against myocardial infarction through the loss of Rad GTPase

Myocardial infarction (MI) continues to be a leading cause of morbidity and mortality in the US. MI is characterized by a loss of blood flow to the heart, resulting in the development of an infarct, or area of dead tissue, which compromises the contractile function of the myocardium. As a result, the heart is stimulated to hypertrophic growth, leading to maladaptive dilation and heart failure over time. For this reason, strategies that promote the preservation of cardiac function after MI have the potential to positively impact the clinical outcomes of MI patients. A novel therapeutic target is the small GTPase Rad, which our laboratory has recently characterized as an important mediator of contractile function. Rad acts as an inhibitor to the L-type calcium channel, and deletion of Rad in mice has been shown to improve conductance and enhance calcium homeostasis in isolated ventricular myocytes. Further, these changes have been shown to promote better function, increasing fractional shortening in isolated ventricular myocytes, elevating +dP/dt in isolated working hearts, and improving ejection fraction in intact animals, without accompanying pathological phenotypes. The hypothesis of this project is to determine if these changes protect the heart from remodeling associated with MI. In order to answer this question, isolated hearts and intact animals that lack Rad expression will be subjected to global no-flow ischemia and ligation of the left anterior descending (LAD) artery, respectively. Infarct and scar development, intraventricular chamber and wall dimensions, and cardiac function will be measured, and ventricular myocytes from MI-subjected hearts will be evaluated for the preservation of calcium homeostasis and response to adrenergic stimulation. It is expected that loss of Rad will promote contractile function sufficiently to preserve cardiac output after MI, and obviate the need for compensatory remodeling. These findings have the potential identify a novel candidate for inotropic therapy that will improve the outcomes of MI patients, and may have implications for the treatment of other diseases of systolic dysfunction.