(Verbatim from the application): Myocardial ischemia/reperfusion (I/R) is a potent stimulus which induces both apoptosis and necrosis of cardiac myocytes. Although apoptosis should be a purposeful behavior of the cells, considering the limited capacity of cell proliferation in adult cardiac myocytes, stimulation of myocyte apoptosis may lead to reduced cardiac function. Thus, understanding the signaling mechanism of apoptosis by L'R is clinically important. Myocardial I/R activates stress-responsive mitogen activated protein kinases (SR-MAPKs), including iNKs and p38-MAPKS. Interestingly, upstream activators of SR-MAPKs, such as MEKK1 and Mstl, are cleaved, possibly through caspases, and activated in response to I/R. It is known in many cell types that these truncated forms of the protein kinases exhibit higher activities and stimulate apoptosis, thereby initiating positive feedback mechanism between """"""""death"""""""" and """"""""SR-MAPK"""""""" pathways. Although there are close relations between apoptosis and SR-MAPKs, the involvement of """"""""death"""""""" signaling pathways in YR-induced activation of SR-MAPKs, and conversely the role of """"""""SR-MAPKS"""""""" in hR induced myocyte apoptosis, remain unclear. We therefore hypothesize that myocardial YR initiates an interaction between the """"""""death"""""""" signaling pathways and the """"""""SR-MAPKs"""""""" pathways, which amplifies apoptosis of cardiac myocytes. Cleavage and activation of MEKK1 and Mstl by caspases are the nodal points of the interaction between two pathways, and such an amplification mechanism plays an essential role in YR-induced myocyte apoptosis. Using molecular biological techniques and adenovirus-mediated transduction in both in vivo and in vitro models of I/R as well as transgenic animals, we will study signaling mechanisms of myocyte apoptosis at both organ and cellular levels. In particular, we will ask 1) if caspases are involved in cleavage/activation of MEKK1 and Mst 1 by I/R; 2) if activation of SR-MAPKs, including caspase-cleaved MEKK1 and Mstl, is sufficient to promote apoptosis; 3) if activation/cleavage of SR-MAPKs is required for cardiac myocyte apoptosis by YR. Our study will contribute to the understanding of the mechanism of cardiac myocyte apoptosis by hR and may provide clues to prevent myocyte loss and reduced cardiac function after myocardial I/R.
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