Signaling Mechanisms in Ischemic Preconditioning Interaction of PKC and MitoKATP in the Inner Membrane of Mitochondria

The cardiac “warm up” phenomenon, described more than 50 years ago in patients with coronary artery disease, refers to improvement in cardiac symptoms and physical performance following exposure to short periods of ischemia.1 Several mechanisms, such as adaptive reduction in oxygen consumption by the ischemic myocardial region, improved oxygen supply via collateral recruitment or dilation of the stenotic vessel, and activation of an intrinsic phenomenon called ischemic preconditioning (IPC) have been proposed to account for this phenomenon. IPC refers to a process in which brief periods of ischemia improves the ability of the heart to tolerate subsequent prolonged ischemic periods.3 It was first identified in the heart in 1986 by Murry et al,2 and has since been demonstrated in various experimental and animal models.3 Several triggers have been proposed for IPC, including adenosine, bradykinin, protaglandins, opiod receptors, nitric oxide, and Ca .4 These triggers lead to the activation of several intracellular pathways that ultimately protect myocardial cells against injury. Although the details of these pathways have not been totally characterized, mitochondria have been shown to be key mediators of IPC. Specifically, the opening of a mitochondrial channel, called the mitochondrial ATP-sensitive potassium channel or mitoKATP is believed to be critical for the induction of IPC; drugs that activate this channel protect against ischemia and inhibitors of mitoKATP reverse these protective effects.5 The signaling pathways that lead to the activation of mitoKATP are still under investigation.5 In a recent article, Oldenburg et al demonstrated that in isolated rabbit adult cardiomyocytes, bradykinin increased the levels of reactive oxygen species (ROS) and this effect was reversed by inhibitors of both mitoKATP and protein kinase G (PKG).6 Subsequent studies demonstrated that mitoKATP can be activated by the addition of exogenous cGMP and PKG, and that this effect is reversed by inhibitors of protein kinase C (PKC).7 These results suggest that PKG transmits the cardioprotective signal to mitoKATP through a PKC-dependent pathway. It is unclear how this signal is transmitted and which isoforms of PKC are involved in this process. In this issue of Circulation Research, Jabůrek et al, demonstrate in a series of elegant studies that mitoKATP and PKC directly interact in the inner mitochondrial membrane, and that PKC is required for the opening of mitoKATP. They first demonstrate the presence of PKC in highly enriched mitochondrial fractions. Subsequently, they show that PKC activators induce the opening of mitoKATP, while its inhibitors and a protein phosphatase reverse these effects. The PKC family of enzymes play a role in several cellular signal transduction pathways and is implicated in numerous physiological and pathological processes.9 Thus far, 11 members of the PKC family have been characterized. These proteins are divided into 3 groups based on their responsiveness to diacylglycerol (DAG) or Ca for enzyme activity. The , I, II, and isozymes are both DAGand Ca dependent, while the , , , and are only DAG-dependent and do not need Ca for activity. The atypical PKCs ( and ) are neither DAGnor Ca -dependent and require lipidderived molecules for activity.9 The potential role of PKC enzymes in cardioprotection has been the subject of many investigations. To evaluate the role of the individual isoforms of PKCs in cardioprotection, recent studies have used isozyme-specific modulators as well as transgenic and knockout mice of specific PKC isozymes. PKC isozymes translocate to distinct cellular locations after activation by binding to their specific anchoring proteins, called receptor for activated C-kinase or RACKs.10 Peptides against the RACK binding site of each PKC isozymes can inhibit the translocation and activity of the corresponding enzyme and have been used as isozyme-specific inhibitors.11 Peptide activators promote PKC isozymes to translocate to a specific subcellular location by mimicking the function of isozyme-specific RACKs.11 Ping et al demonstrated that all 11 isoforms of PKC are present in rabbit myocardium and that IPC activates the and isoforms.12 Subsequent studies have supported a major role of PKC in IPC. Mochly-Rosen’s group has demonstrated that PKC is activated in IPC,13 and that treatment with a PKC selective inhibitor during preconditioning reverses the protective effects of IPC.13,14 Furthermore, overexpression of PKC in the heart of transgenic mice resulted in a lesser degree of ischemic damage,15 and PKC knockout mice did not retain the protective effects of preconditioning.16 These results suggest that PKC is required and sufficient for the protective effects of IPC in the heart. Another PKC isozyme, PKC , also plays a role in myocardial cell death. However, unlike PKC , this isozyme is believed to promote damage from an ischemic insult. Activation of PKC causes a higher degree of cell death in response to ischemia and its inhibition The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Cardiology, Department of Medicine, Northwestern University Medical Center, Chicago, Ill. Correspondence to: Hossein Ardehali, Tarry 12–725, 303 E Chicago Ave, Chicago, IL 60611. E-mail [email protected] (Circ Res. 2006;99:798-800.) © 2006 American Heart Association, Inc.