Interaction between death and MAPK pathways with myocardial ischemia

心肌缺血/再灌注（I/R）是一种诱导心肌细胞凋亡和坏死的有效刺激。虽然细胞凋亡应该是细胞的一种有目的的行为，但考虑到成人心肌细胞有限的增殖能力，心肌细胞凋亡可能导致心功能降低。因此，通过I/R了解细胞凋亡的信号机制是很重要的。心肌I/R激活应激反应性丝裂原活化蛋白激酶表现出更高的活性，刺激细胞凋亡，从而启动“死亡”通路和“SR-MAPK”通路之间的正反馈机制。尽管细胞凋亡与SR-MAPKs之间存在密切的关系，但“死亡”信号通路在I/R诱导的SR-MAPKs激活中的运动，以及反过来“SR-MAPKs”在I/R诱导的肌细胞凋亡中的作用尚不清楚。我们假设心肌I/R启动了“死亡”信号通路和“SR- MAPKs”通路之间的相互作用，从而放大了心肌细胞的凋亡。caspases对MEKK1和Mst1的裂解和激活是两条通路相互作用的节点，这种扩增机制在I/R诱导的肌细胞凋亡中起着至关重要的作用。利用分子生物学技术和腺病毒介导的转导在体内和体外I/R模型，以及转基因动物和慢性仪器意识猪I/R模型中，我们将在器官和细胞水平上研究肌细胞凋亡的信号机制。我们将问1)半胱天冬酶是否通过I/R参与了MEKK1和Mst1的切割/激活；2) SR- MAPKs（包括caspase-cleaved MEKK1和Mst1）的激活是否足以促进细胞凋亡；3) SR-MAPKs（包括caspase/cleaved MEKK1和Mst1）的激活/裂解是否足以促进细胞凋亡；3)心肌细胞I/R凋亡是否需要SR-MAPKs的激活/裂解。我们的研究将有助于理解心肌细胞I/R凋亡的机制，并可能为防止心肌细胞损失和心功能降低改变心肌I/R提供线索。

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.