UNIVERSITY OF MIAMI
Grant: $478,125 - National Institutes of Health - Jun. 1, 2009
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Award Description: The mean time to reperfusion of acute myocardial infarction (AMI) patients in the USA is 3-4h. The metabolic activity within the ischemic tissue over this period is a major determinant of outcome and is critically influenced by the glycemic and insulin-responsive status of the subject. Inadequate glucose-stimulated insulin production and/or insulin resistance of muscle and liver cause hyperglycemia. We hypothesize that a major component of the exacerbated injury that accompanies myocardial ischemia/reperfusion in hyperglycemic subjects is caused by an early switch in the function of c-Jun-N-terminal kinase (JNK) from protective to injurious. We have described an energy-dependent switch in the function of JNK in cultured cardiac myocytes. The switch occurred when cardiac myocyte ATP level fell below 50%, a condition that sensitized myocytes to oxidative stress, activated AMPK and increased Akt phosphorylation. We hypothesize that the switch involves differential phosphorylation by JNK of pro-survival Akt on the positive Thr-450 site, and IRS-1 on the inhibitory Ser-307 site. We have confirmed that the switch operates in vivo in both mouse and pig models when the myocardium is subjected to AMI and encounters similar metabolic stress. The in vivo effect is dramatic, JNK inhibition during prolonged ischemia of mouse hearts reduced both apoptosis and infarction by >50%, but the same inhibition imposed on a short ischemic episode increased both apoptosis and infarction by >10-fold. Because >50% of injury caused by severe ischemia/reperfusion is regulated by JNK, the switch is potentially a major contributor to the outcome of AMI. New Preliminary Results indicate that JNK-mediated protection against brief ischemia is lost in the hearts of diabetic db/db mice. In this revised application we will investigate the role of the JNK switch and other inflammatory mediators in the exacerbated infarction of hyperglycemic mouse and pig hearts. We will characterize the metabolic signals that mediate switching and determine the death/survival pathways that are affected. In Aim 1 we will quantify infarction and programmed death, and remodeling over time in 3 models of hyperglycemia by TTC, immunostaining, echocardiography and MRI. In Aim 2 we will use 31P-NMR to determine the precise metabolic parameters that regulate JNK switching in normal and hyperglycemic hearts during AMI. In Aim 3 we will investigate the molecular mechanisms of JNK-regulated death and the targets that determine survival or death. In Aim 4 we will compare infarction and cell death during brief and prolonged ischemia and the effects of JNK inhibitor in normal and diabetic swine.
Project Description: We have completed 50% of aims 1-3. A manuscript is under review at the highly prestigious journal Nature Medicine, describing these results, and the results will be presented at the American Heart Association Scientific Sessions, in November 2009.
Jobs Summary: The continued employment of six individuals is possible because of the Recovery Act funding. Otherwise their time and effort would have to be reduced and the positions possibly lost. (Total jobs reported: 3)
Project Status: Less Than 50% Completed
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