Bradykinin prevents reperfusion injury by targeting mitochondrial permeability transition pore through glycogen synthase kinase 3β

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• 作者：Sung-Sik Park ; Hong Zhao ; Robert A. Mueller and Zhelong Xu
• 关键词：Bradykinin ; Reperfusion injury ; mPTP ; GSK-3β
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2006
• 出版时间：May 2006
• 年：2006
• 卷：40
• 期：5
• 页码：708-716
• 全文大小：599 K

文摘

Although bradykinin has been demonstrated to protect the heart at reperfusion, the detailed cellular and molecular mechanisms that mediate the protection remain elusive. Here we aimed to determine whether bradykinin protects the heart at reperfusion by modulating the mitochondrial permeability transition pore (mPTP) opening through glycogen synthase kinase 3β (GSK-3β). Bradykinin given at reperfusion reduced infarct size in isolated rat hearts subjected to 30 min regional ischemia followed by 2 h of reperfusion. The infarct-limiting effect of bradykinin was reversed by atractyloside, an opener of the mPTP, suggesting that bradykinin may protect the heart at reperfusion by modulating the mPTP opening. In support of this observation, bradykinin prevented the collapse of mitochondrial membrane potential (ΔΨ_m), an index of the mPTP opening. Bradykinin increased GSK-3β phosphorylation at reperfusion, and the selective inhibitor of GSK-3β SB216763 reduced infarct size and prevented the loss of ΔΨ_m by mimicking the effect of bradykinin. The effect of bradykinin on GSK-3β phosphorylation was blocked by wortmannin and LY294002, and bradykinin increased Akt phosphorylation at reperfusion. Further experiments showed that the MEK inhibitor PD98059 prevented the effect of bradykinin on GSK-3β. However, the mTOR/p70s6K pathway inhibitor rapamycin did not alter bradykinin-induced GSK-3β phosphorylation and bradykinin failed to alter phosphorylation of either mTOR or p70s6K at reperfusion. Taken together, these data suggest that bradykinin protects the heart at reperfusion by modulating the mPTP opening through inhibition of GSK-3β. The PI3-kinase/Akt pathway and ERK, but not the mTOR/p70s6K pathway account for the suppression of GSK-3β by bradykinin.