Heart failure is one (1) of the most significant health issues in the US with ischemia/myocardial infarct as one (1) of its leading causes. Pro-inflammatory genes, including TNFalpha, IL-6 and COX2 are highly induced and thought to contribute to pathological decompensation in heart failure following ischemia/reperfusion injury. However, the signaling mechanism mediating their induction in cardiomyocytes is not yet well established. In our preliminary studies, we find that activation of stress-activated mitogen activated protein (MAP) kinase, p38 is highly correlated with ischemia/reperfusion. Targeted activation of p38 activities leads to induction of pro-inflammatory genes in cardiomyocytes and pathological remodeling in intact heart. These findings lead to our current hypothesis that p38 MAP kinase activation contributes to specific aspects of cardiac pathology during ischemia/myocardial infarction via targeted regulation of stress-response genes and inflammatory cytokine in cardiomyocytes. In this proposal, we will rigorously test this hypothesis by achieving the following 3 specific aims: 1) To determine the functional role of p38 in regulating inflammatory gene induction and cardiac remodeling in vivo. 2).To determine the physiological role of p38 pathway in inflammatory gene induction and cardiac injury following myocardial infarction. 3) To determine the molecular basis of p38 function and regulation in cardiomyocytes. Accomplishing these aims will establish the functional significance of p38 pathway in ischemic heart failure and add important new insight to the molecular mechanisms of pathological remodeling in failing heart. More importantly, it will provide critical information about p38 pathway as a potential new therapeutic target to treat myocardial infarction and ischemic heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Varghese, Jamie
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Yokota, Tomohiro; Wang, Yibin (2016) p38 MAP kinases in the heart. Gene 575:369-376
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