Signaling Mechanisms in Ischemic Preconditioning
2006; Lippincott Williams & Wilkins; Volume: 99; Issue: 8 Linguagem: Inglês
10.1161/01.res.0000247029.31997.a4
ISSN1524-4571
Autores Tópico(s)Cardiac Arrest and Resuscitation
ResumoHomeCirculation ResearchVol. 99, No. 8Signaling Mechanisms in Ischemic Preconditioning Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBSignaling Mechanisms in Ischemic PreconditioningInteraction of PKCε and MitoKATP in the Inner Membrane of Mitochondria Hossein Ardehali Hossein ArdehaliHossein Ardehali From the Division of Cardiology, Department of Medicine, Northwestern University Medical Center, Chicago, Ill. Originally published13 Oct 2006https://doi.org/10.1161/01.RES.0000247029.31997.a4Circulation Research. 2006;99:798–800The 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.3Several triggers have been proposed for IPC, including adenosine, bradykinin, protaglandins, opiod receptors, nitric oxide, and Ca2+.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.5The 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 PKCε directly interact in the inner mitochondrial membrane, and that PKCε is required for the opening of mitoKATP.8 They first demonstrate the presence of PKCε in highly enriched mitochondrial fractions. Subsequently, they show that PKCε 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 Ca2+ for enzyme activity. The α, βI, βII, and γ isozymes are both DAG- and Ca2+-dependent, while the ε, δ, θ, and η are only DAG-dependent and do not need Ca2+ for activity. The atypical PKCs (ζ and λ) are neither DAG- nor Ca2+-dependent and require lipid-derived molecules for activity.9The 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.11Ping et al demonstrated that all 11 isoforms of PKC are present in rabbit myocardium and that IPC activates the ε and η isoforms.12 Subsequent studies have supported a major role of PKCε in IPC. Mochly-Rosen's group has demonstrated that PKCε is activated in IPC,13 and that treatment with a PKCε selective inhibitor during preconditioning reverses the protective effects of IPC.13,14 Furthermore, overexpression of PKCε in the heart of transgenic mice resulted in a lesser degree of ischemic damage,15 and PKCε knockout mice did not retain the protective effects of preconditioning.16 These results suggest that PKCε is required and sufficient for the protective effects of IPC in the heart. Another PKC isozyme, PKCδ, also plays a role in myocardial cell death. However, unlike PKCε, this isozyme is believed to promote damage from an ischemic insult. Activation of PKCδ causes a higher degree of cell death in response to ischemia and its inhibition leads to protection in isolated cardiomyocytes and intact hearts.17Although the signaling mechanisms that link PKC to ischemic preconditioning are not completely characterized, several pathways have been proposed (Figure). These include generation of free radicals, changes in the levels of the pro- and antiapoptotic proteins of Bcl-2 family, and activation of the mitoKATP.18 ROS that are produced during both ischemia and reperfusion have deleterious effects on cardiomyocytes. However, these molecules are also believed to activate multiple signaling pathways, including the activation of PKC enzymes.19,20 ROS have been shown to lead to PKCδ activation and translocation.19,20 However, there is currently no evidence linking ROS formation to PKCε mediated cardioprotection. PKCε is also shown to enhance the phosphorylation of a proapoptoic Bcl-2 related protein (Bcl-2 associated death domain or BAD), inactivating it and blocking its ability to induce apoptosis.21 The expression of Bcl-2 protein may also be regulated by PKCε.22 However, a recent study showed that although knockdown of PKCε induces apoptosis in glioma cells, it does not affect the expression of Bcl-2 or Bax.23Download figureDownload PowerPointSchematic diagram outlining current thinking of the molecular mechanism of cardioprotection through PKCε and mitoKATP. PKCε activation by different mechanisms would lead to its translocation into the mitochondria and interaction with mitoKATP, leading to cardioprotection. It is also shown to phosphorylate and inactivate the proapoptotic protein BAD. PLC, phospholipase C; PLD, phospholipase D; NO, nitric oxide; NOS, nitric oxide synthase.A number of previous studies provided evidence for a possible link between PKC and mitoKATP in IPC. Hassouna et al demonstrated that PKCε inhibitors block protection from IPC, and that diazoxide (a mitoKATP activator) did not affect the phosphorylation of PKCε, suggesting that PKCε may act upstream of mitoKATP.24 Korge et al has shown that a nonspecific PKC activator can induce cardioprotection and this effect was reversed by mitoKATP inhibitors.25 Finally, PKCε is shown to interact with several mitochondrial proteins, suggesting that it may translocate into the mitochondria.26 The current manuscript for the first time shows that PKCε interacts and activates mitoKATP in the inner membrane of the mitochondria.Although the findings by Jaburek et al are interesting and have addressed an important question, they have also raised many new questions. What is the mechanism for PKCε translocation into the mitochondria? Does PKCε phosphorylate any protein components of mitoKATP? Is there a RACK for PKCε in the mitochondria? Besides PKG, what other pathways lead to PKC-mediated activation of mitoKATP? The answer to these questions may better delineate the protective roles of PKCε and mitoKATP.In summary, the current manuscript by Jaburek et al demonstrates that mitoKATP and PKCε functionally interact with each other in the inner membrane of the mitochondria. These results improve our understanding of the signals that leads to the opening of mitoKATP and the protective effects of IPC (Figure). Although the mechanism of PKCε activation of mitoKATP is not totally clear, it is tempting to speculate that it directly phosphorylates the protein components of the channel, resulting in the opening of the channel and entrance of K+ into the mitochondria. This potential mechanism for the regulation of the mitoKATP channel remains to be elucidated.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.I thank Drs Mike Burke and Kannan Mutharasan for critical reading of the manuscript.Sources of FundingH.A. is supported by NIH grant K08 HL079387 and grants from the Schweppe foundation and the Northwestern Memorial Foundation.DisclosuresNone.FootnotesCorrespondence to: Hossein Ardehali, Tarry 12–725, 303 E Chicago Ave, Chicago, IL 60611. E-mail [email protected] References 1 Tomai F. Warm up phenomenon and preconditioning in clinical practice. Heart. 2002; 87: 99–100.CrossrefMedlineGoogle Scholar2 Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986; 74: 1124–1136.CrossrefMedlineGoogle Scholar3 Kloner RA, Bolli R, Marban E, Reinlib L, Braunwald E. 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October 13, 2006Vol 99, Issue 8 Advertisement Article InformationMetrics https://doi.org/10.1161/01.RES.0000247029.31997.a4PMID: 17038649 Originally publishedOctober 13, 2006 Keywordsprotein kinase C-εprotein kinase GRACKmitoKATPischemic preconditioningPDF download Advertisement
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