The overall goals of Project 3 are to investigate the basic mechanisms underlying the disproportionately poor prognosis in blacks with ischemic heart disease (IHD), and to test the efficacy of therapies targeted at these mechanisms. Blacks with IHD are subject to episodes of ischemia and reperfusion that generate reactive oxygen species (ROS), resulting in myocardial oxidant injury. Endogenous myocardial defense against oxidant stress is mediated primarily by glucose-6-phosphate dehydrogenase (G6PD). G6PD deficiency in the most common enzymopathy in humans, and is known to be especially prevalent in blacks. In addition, blacks also have a high rate of salt-sensitive hypertension and ventricular hypertrophy, two common risk factors for IHD. In the last cycle of this SCOR program, salt-sensitive hypertension was shown to be due, in part, to a reduced availability largely as a consequence of inactivation of NO by elevated levels of ROS. Our central hypothesis is that G6PD deficiency exacerbates injury from ischemia- reperfusion and may, in part, account for the worse prognosis in blacks with IHD. Furthermore, increased ROS levels secondary to G6PD deficiency may exacerbate salt-sensitive hypertension and hypertrophy, and worsens ischemia-reperfusion injury in hypertrophied hearts. Mice deficient in G6PD will be studied at three levels of physiologic integration: intact animals, isolated perfused hearts and isolated myocytes. In intact mice, the consequences of G6PD deficiency on the cardiovascular system will be assessed following coronary ligation and reperfusion. In isolated hearts, systolic and diastolic function will be measured during ischemia reperfusion, along with NMR spectroscopic measurements of high energy phosphate metabolism, pentose phosphate flux, and glutathione redox state. In isolated myocytes undergoing hypoxia-reoxygenation, changes in contractility will be measured simultaneously with cell calcium with ROS levels by fluorescent probes. The efficacy and mechanisms of action of clinically relevant treatment (antioxidants, increased pentose phosphate pathway flux, chronic exercise training) that may protect against ischemia-reperfusion injury in G6PD deficient myocardium will be determined. Data from this project will provide new information regarding the basic mechanisms underlying myocardial injury, as well as identify potential treatment strategies for blacks with IHD.
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