Reactive Oxygen Species as Mediators of Signal Transduction in Ischemic Preconditioning

Abstract

Ischemic preconditioning (IPC) is a most powerful endogenous mechanism for myocardial protection against ischemia/reperfusion injury. It is now apparent that reactive oxygen species (ROS) generated in the mitochondrial respiratory chain act as a trigger of IPC. ROS mediate signal transduction in the early phase of IPC through the posttranslational modification of redox-sensitive proteins. ROS-mediated activation of Src tyrosine kinases serves a scaffold for interaction of proteins recruited by G protein-coupled receptors and growth factor receptors that is necessary for amplification of cardioprotective signal transduction. Protein kinase C (PKC) plays a central role in this signaling cascade. A crucial target of PKC is the mitochondrial ATP-sensitive potassium channel, which acts as a trigger and a mediator of IPC. Mitogen-activated protein (MAP) kinases (extracellular signal-regulated kinase, p38 MAP kinase, and c-Jun NH₂-terminal kinase) are thought to exist downstream of the Src-PKC signaling module, although the role of MAP kinases in IPC remains undetermined. The late phase of IPC is mediated by cardioprotective gene expression. This mechanism involves redox-sensitive activation of transcription factors through PKC and tyrosine kinase signal transduction pathways that are in common with the early phase of IPC. The effector proteins then act against myocardial necrosis and stunning presumably through alleviation of oxidative stress and Ca²⁺ overload. Elucidation of IPC-mediated complex signaling processes will help in the development of more effective pharmacological approaches for prevention of myocardial ischemia/reperfusion injury.