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.
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