Myocardial ischemia/reperfusion (I/R) is a potent stimulus which induces apoptosis and necrosis of cardiac myocytes. Although apoptosis should be a purposeful behavior of cells, considering the limited capacity of cell proliferation in adult cardiac myocytes, myocyte apoptosis may lead to reduced cardiac function. Thus, understanding the signaling mechanism of apoptosis by I/R is important. Myocardial I/R activates stress- responsive mitogen activated 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 movement of """"""""death"""""""" signaling pathways in I/R-induced activation of SR-MAPKs, and conversely the role of """"""""SR-MAPKs"""""""" in I/R induced myocyte apoptosis, remain unclear. We hypothesize that myocardial I/R 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 Mst1 by caspases are the nodal points of the interaction between two pathways, and such an amplification mechanism plays an essential role in I/R induced myocyte apoptosis. Using molecular biological techniques and adenovirus- mediated transduction in in vivo and in vitro models of I/R as well as transgenic animals and the chronically instrumented conscious pig model of I/R, we will study signaling mechanisms of myocyte apoptosis at both organ and cellular levels. We will ask 1) if caspases are involved in cleavage/activation of MEKK1 and Mst1 by I/R; 2) if activation of SR- MAPKs, including caspase-cleaved MEKK1 and Mst1, is sufficient to promote apoptosis; 3) if activation/cleavage of SR-MAPKs, including caspase/cleaved MEKK1 and Mst1, is sufficient to promote apoptosis; 3) if activation/cleavage of SR-MAPKs is required for cardiac myocyte apoptosis by I/R. Our study will contribute to the understanding of the mechanism of cardiac myocyte apoptosis by I/R and may provide clues to prevent myocyte loss and reduced cardiac function alter myocardial I/R.
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