Signaling in late preconditioning : involvement of mitochondrial K(ATP) channels.

Lethal injury to the heart can be dramatically blunted by brief periods of prior ischemia.1 Such an endogenous cardioprotective mechanism, known as ischemic preconditioning (IPC), exists in all species examined to date, including humans.2 IPC occurs in a biphasic pattern of myocardial protection: an early phase (classic IPC), which develops immediately and lasts approximately 2 hours after the IPC stimulus, and a delayed phase (late IPC or second window of protection), which reappears after 24 hours and lasts at least 72 hours.3,4 Despite intensive investigation, the cellular mechanism of IPC still remains obscure, although important clues are beginning to emerge. A number of substances and signaling pathways have been proposed to be involved in mediating the cardioprotective effect of IPC (reviewed in Downey and Cohen5). Nevertheless, considerable evidence has suggested that ATP-sensitive K (KATP) channels may serve as the end effectors in this process.6 Although the cardioprotective effects were initially attributed to plasma membrane KATP channels, the degree of action potential shortening can be divorced from the extent of protection.7,8 Instead, it now seems much more likely that KATP channels in mitochondrial inner membrane (mitoKATP channels) are the dominant players. The studies of the mitoKATP channel were facilitated by the identification of a selective opener and a selective blocker of mitoKATP channels (selective relative to cardiac sarcolemmal KATP channels, by at least three orders of magnitude), namely diazoxide and 5-hydroxydecanoate.9,10 The mitoKATP channel opener diazoxide mimics the infarct size–limiting effects of classic IPC, whereas the mitoKATP channel blocker 5-hydroxydecanoate obliterates the beneficial effects of conditioning ischemia.9,11 Thus, mitoKATP channels have emerged as the likely effectors of classic IPC. The underlying pathophysiology and mechanisms between early and delayed phases of cardioprotection are likely to differ, with posttranslational modifications dominating the early phase; given the timing, changes in gene expression should only come to play in the delayed phase. Interestingly, the mitoKATP channel now appears to feature prominently in both phases of protection. Bernardo et al12 have reported that the mitoKATP channel blocker 5-hydroxydecanoate abolishes late IPC in the rabbit heart. Fryer et al13 also found that opioid-induced delayed protection in the rat heart was lost by 5-hydroxydecanoate. Moreover, in this issue of Circulation Research, Takashi et al14 report that the mitoKATP channel opener diazoxide mimics late IPC and reduces the infarct size after 24 hours in rat hearts. These studies suggest that mitoKATP channels may be the site of action responsible for the cardioprotective effect of late IPC. The study by Takashi et al14 demonstrated that chelerythrine, a potent protein kinase C (PKC) inhibitor, abolished the diazoxide-induced delayed protection, suggesting that the mitoKATP channel induces late IPC via PKC-mediated signaling pathway. The links between PKC and mitoKATP channels were previously addressed by Sato et al,10 in which exposure to phorbol 12-myristate 13-acetate, an activator of PKC, potentiated and accelerated the diazoxide-induced opening of mitoKATP channels. Therefore, it is now apparent that activation of PKC figures prominently in the signal transduction cascade of both early and late phases of IPC. IPC causes isozyme-selective translocation of PKC. Although, in the present study, Takashi et al14 did not identify the PKC isozyme responsible for the PKC-mitoKATP channel signaling pathway, Wang and Ashraf15 recently reported that PKC-d is translocated to mitochondria in rat myocytes. However, in another study, PKC-e but not PKC-d has been argued to be responsible for the early phase of IPC in rabbit cardiomyocytes.16 Further studies are still necessary to determine the similarity or difference concerning PKC isozymes responsible for the activation of the mitoKATP channel in classic versus late IPC. Bolli et a117 have addressed a possible role for nitric oxide (NO) in mediating late IPC. In this issue of Circulation Research, Dawn et al18 demonstrate that protein tyrosine kinase is necessary to trigger and to mediate late IPC against myocardial stunning. Moreover, they show that protein tyrosine kinase signaling is essential for the augmentation of inducible NO synthase (iNOS) activity during the late phase of IPC, indicating that iNOS is involved as a downstream element of protein tyrosine kinase. Protein tyrosine kinase is reported to be downstream of protein kinase C for classic as well as late IPC in rabbits.19,20 It remains unknown whether PKC directly activates mitoKATP channels or does so indirectly through a tyrosine kinase–mediated pathway. How might NO interact with mitoKATP channels? New links between NO and these candidate effectors are reported by Sasaki et al,21 who demonstrated that exposure of myocytes to an NO donor directly activates mitoKATP channels as well as potentiates the ability of diazoxide to open these channels. The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Physiology, Oita Medical University, Oita, Japan. Correspondence to Toshiaki Sato, MD, PhD, Department of Physiology, Oita Medical University, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan. E-mail [email protected] (Circ Res. 1999;85:1113-1114.) © 1999 American Heart Association, Inc.