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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062311-08
Application #
7248038
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Liang, Isabella Y
Project Start
2000-05-15
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
8
Fiscal Year
2007
Total Cost
$219,741
Indirect Cost
Name
University of California Los Angeles
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Yokota, Tomohiro; Wang, Yibin (2016) p38 MAP kinases in the heart. Gene 575:369-376
Sun, Haipeng; Gao, Chen; Wang, Yibin (2015) A H(a)rd Way to Adapt in Cardiac Hypertrophy. Circ Res 117:484-6
Foster, William H; Tidball, James G; Wang, Yibin (2012) p38? activity is required for maintenance of slow skeletal muscle size. Muscle Nerve 45:266-73
Sun, Haipeng; Wang, Yibin (2012) Prostaglandin E2 in remote control of myocardial remodeling. Circulation 125:2818-20
Sun, Haipeng; Wang, Yibin (2011) Restriction of big hearts by a small RNA. Circ Res 108:274-6
Marber, Michael S; Rose, Beth; Wang, Yibin (2011) The p38 mitogen-activated protein kinase pathway--a potential target for intervention in infarction, hypertrophy, and heart failure. J Mol Cell Cardiol 51:485-90
Streicher, John M; Ren, Shuxun; Herschman, Harvey et al. (2010) MAPK-activated protein kinase-2 in cardiac hypertrophy and cyclooxygenase-2 regulation in heart. Circ Res 106:1434-43
Rose, Beth A; Force, Thomas; Wang, Yibin (2010) Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiol Rev 90:1507-46
Streicher, John M; Kamei, Kenichiro; Ishikawa, Tomo-o et al. (2010) Compensatory hypertrophy induced by ventricular cardiomyocyte-specific COX-2 expression in mice. J Mol Cell Cardiol 49:88-94
Ota, Asuka; Zhang, Jun; Ping, Peipei et al. (2010) Specific regulation of noncanonical p38alpha activation by Hsp90-Cdc37 chaperone complex in cardiomyocyte. Circ Res 106:1404-12

Showing the most recent 10 out of 27 publications