Downey James M, Davis Amanda M, Cohen Michael V
Department of Physiology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.
Heart Fail Rev. 2007 Dec;12(3-4):181-8. doi: 10.1007/s10741-007-9025-2.
Ischemic preconditioning renders the heart resistant to infarction from ischemia/reperfusion. Over the past two decades a great deal has been learned about preconditioning's mechanism. Adenosine, bradykinin, and opioids act in parallel to trigger the preconditioned state and do so by activating PKC. While adenosine couples directly to PKC through the phospholipases, bradykinin and opioids do so through a complex pathway that includes in order: phosphatidylinositol 3-kinase (PI3-kinase), Akt, nitric oxide synthase, guanylyl cyclase, PKG, opening of mitochondrial K(ATP) channels, and activation of PKC by redox signaling. There are even differences between the opioid and bradykinin coupling as the former activates PI3-kinase through transactivation of the epidermal growth factor receptor while the latter has an unknown coupling mechanism. Protection stems from inhibition of formation of mitochondrial permeability transition pores early in reperfusion through activation of the survival kinases, Akt and ERK. These kinases are activated as a result of PKC somehow promoting signaling from adenosine A(2) receptors early in reperfusion. The survival kinases are thought to inhibit pore formation by phosphorylating GSK-3beta. The reperfused heart requires the support of the protective signals for only about an hour after which the ischemic injury is repaired and the signals are no longer needed.
缺血预处理可使心脏对缺血/再灌注引起的梗死具有抗性。在过去二十年中，人们对预处理的机制有了很多了解。腺苷、缓激肽和阿片类物质协同作用以触发预处理状态，并通过激活蛋白激酶C（PKC）来实现。腺苷通过磷脂酶直接与PKC偶联，而缓激肽和阿片类物质则通过一条复杂的途径来实现，该途径依次包括：磷脂酰肌醇3激酶（PI3激酶）、Akt、一氧化氮合酶、鸟苷酸环化酶、蛋白激酶G（PKG）、线粒体ATP敏感性钾通道开放以及通过氧化还原信号激活PKC。阿片类物质和缓激肽的偶联甚至存在差异，因为前者通过表皮生长因子受体的反式激活来激活PI3激酶，而后者的偶联机制尚不清楚。保护作用源于在再灌注早期通过激活存活激酶Akt和细胞外信号调节激酶（ERK）来抑制线粒体通透性转换孔的形成。这些激酶的激活是由于PKC在再灌注早期以某种方式促进了腺苷A2受体的信号传导。存活激酶被认为通过磷酸化糖原合成酶激酶-3β（GSK-3β）来抑制孔的形成。再灌注后的心脏仅在大约一小时内需要保护信号的支持，此后缺血损伤得到修复且不再需要这些信号。
