Heart failure (HF) is one of the leading causes of mortality and immobility. The development of HF involves persistence of various stresses on cardiomyocytes that will lead to cardiac hypertrophy (CH), loss of contractile function and chamber dilation at advanced stage. Stress-activated MAP kinases (SAPKs), mainly consisted of cJun N-terminal kinases (JNK) and p38 kinases, have been implicated as important signaling molecules in a variety of stress responses. We demonstrated in neonatal cardiac myocytes that activation of JNK and p38 beta activities induced hypertrophy and activation of p38 alpha led to cell death. However, the in vivo function of JNK and p38s in the induction of CH and HF has not been established. The focus of this study, therefore, is to determine the in vivo function of JNK and p38 pathways in cardiac hypertrophy and development of HF, and test the hypothesis that activation of JNK and p38 isoforms contributes to specific features of cardiac hypertrophy, dysfunction and failure. The overall strategy for the study is to use efficient gene transfer technique and transgenic approach to specifically manipulate individual JNK and p38 activities in mouse heart, and to determine the effects of such manipulation on the development of CH and CF through comprehensive molecular, cellular and physiological analysis. Specifically, the proposed study will accomplish the following aims: 1). To determine the effects of specific activation of JNK and p38 MAP kinases on cardiac function and morphology in vivo. 2). To determine whether JNK and p38 activation is required in the development of CH and HF under physiological (pressure-overload) and genetic manipulations (Ras activation). 3). To determine the in vivo function of p38 alpha and beta isoforms in cardiac myocytes. The proposed study will provide a broad and comprehensive analysis for the functional roles of JNK and p38s in the development of CH and HF, covering levels from molecular and single cell to whole organ physiology. The expected results will contribute to the overall understanding of the underlined mechanisms of heart failure and may ultimately lead to identification of novel approaches for better treatment of this disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062311-03
Application #
6537547
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Liang, Isabella Y
Project Start
2000-05-15
Project End
2004-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
3
Fiscal Year
2002
Total Cost
$222,750
Indirect Cost
Name
University of Maryland Baltimore
Department
Physiology
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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

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