© 1999 American Heart Association, Inc.
Editorials |
Signaling in Late Preconditioning
Involvement of Mitochondrial KATP Channels
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 tsato{at}oita-med.ac.jp
Key Words: preconditioning • mitochondria • protein kinase C • protein tyrosine kinase
 |
Introduction |
|---|
 Top Introduction References |
|---|
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-
is translocated to mitochondria in rat myocytes. However,
in another study, PKC-
but not PKC- 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 al17 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. These findings, taken together, provide tangible links among various key elements in the late IPC cascade and implicate mitoKATP channels as the effectors of late IPC.
The question remains as to how the opening of mitoKATP channels might protect myocytes against ischemic damage. It has been proposed that membrane depolarization produced by the K+ entry may reduce mitochondrial Ca2+ entry through the calcium uniport, which results in a reduction in mitochondrial Ca2+ overload. Consistent with this hypothesis, mitoKATP channel openers release Ca2+ from Ca2+-loaded mitochondria.22 Among the more interesting findings in the study by Takashi et al14 was the antiapoptotic effect of diazoxide. They demonstrated that diazoxide decreased cell death by apoptosis, an effect that was antagonized by 5-hydroxydecanoate. In agreement with this study, it has been reported that IPC reduces ischemic injury by decreasing apoptosis in rat hearts.23 Conversely, Holmuhamedov et al22 reported that, in isolated cardiac mitochondria, the mitoKATP channel opening by cromakalim and pinacidil increased matrix volume and released cytochrome c, which may counteract the postulated beneficial action of the mitoKATP channel. These disparate results need to be reconciled in future studies. Perhaps crucial aspects of the apoptotic signaling pathways are disrupted in the process of mitochondrial isolation, in which case complementary studies on intact cells would be valuable.
Evidence is rapidly accumulating that the mitoKATP channel may be the end effector responsible for cardioprotection in both early and late phases of IPC. Future studies of mitoKATP channels are essential in elucidating just how activation of these channels protects against lethal injury in both the early and the delayed phases of IPC.
|
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
|
TopIntroductionReferences |
|---|
1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124–1136.
2. Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet. 1993;342:276–277.[Medline] [Order article via Infotrieve]
3.
Kuzuya T, Hoshida S, Yamashita N, Fuji H, Horie M,
Kodama T, Tada M. Delayed effects of sublethal ischemia on the
acquisition of tolerance to ischemia. Circ Res. 1993;72:1293–1299.
4.
Marber MS, Latchman DS, Walker JM, Yellon DM. Cardiac
stress protein elevation 24 hours after brief ischemia or heat
stress is associated with resistance to myocardial infarction.
Circulation. 1993;88:1264–1272.
5. Downey JM, Cohen MV. Signal transduction in ischemic preconditioning. Adv Exp Med Biol. 1997;430:39–55.[Medline] [Order article via Infotrieve]
6. Gross GJ. ATP-sensitive potassium channels and myocardial preconditioning. Basic Res Cardiol. 1995;90:85–88.[Medline] [Order article via Infotrieve]
7. Grover GJ, Dalonzo AJ, Dzwonczyk S, Parham CS, Darbenzio RB. Preconditioning is not abolished by the delayed rectifier K+ blocker dofetilide. Am J Physiol. 1996;40:H1207–H1214.
8.
Yao Z, Gross GJ. Effects of the
KATP channel opener bimakalim on coronary
blood flow, monophasic action potential duration, and infarct size in
dogs. Circulation. 1994;89:1769–1775.
9.
Liu Y, Sato T, O’Rourke B, Marbán E.
Mitochondrial ATP-dependent potassium channels: novel effectors of
cardioprotection? Circulation. 1998;97:2463–2469.
10.
Sato T, O’Rourke B, Marbán E. Modulation of
mitochondrial ATP-dependent K+ channels by
protein kinase C. Circ Res. 1998;83:110–114.
11.
Baines CP, Liu GS, Birincioglu M, Critz SD, Cohen MV,
Downey JM. Ischemic preconditioning depends on interaction
between mitochondrial KATP channels and actin
cytoskeleton. Am J Physiol. 1999;276:H1361–H1368.
12.
Bernardo NL, D’Angelo M, Okubo S, Joy A, Kukreja RC.
Delayed ischemic preconditioning is mediated by opening of
ATP-sensitive potassium channels in the rabbit heart. Am J
Physiol. 1999;276:H1323–H1330.
13.
Fryer RM, Hsu AK, Eells JT, Nagase H, Gross GJ.
Opioid-induced second window of cardioprotection: potential role of
mitochondrial KATP channels. Circ Res. 1999;84:846–851.
14.
Takashi E, Wang Y, Ashraf M. Activation of
mitochondrial KATP channel elicits late
preconditioning against myocardial infarction via protein kinase C
signaling pathway. Circ Res. 1999;85:1146–1153.
15.
Wang Y, Ashraf M. Role of protein kinase C in
mitochondrial KATP channel-mediated protection
against Ca2+ overload injury in rat
myocardium. Circ Res. 1999;84:1156–1165.
16.
Liu GS, Cohen MV, Mochly-Rosen D, Downey JM. Protein
kinase C- is responsible for the protection of preconditioning
in rabbit cardiomyocytes. J Mol Cell Cardiol. 1999;31:1937–1948.[Medline]
[Order article via Infotrieve]
17. Bolli R, Dawn B, Tang XL, Qiu Y, Ping P, Xuan YT, Jones WK, Takano H, Guo Y, Zang J. The nitric oxide hypothesis of late preconditioning. Basic Res Cardiol. 1998;93:325–338.[Medline] [Order article via Infotrieve]
18.
Dawn B, Xuan YT, Qiu Y, Takano H, Tang XL, Ping P,
Banerjee S, Hill M, Bolli R. Bifunctional role of protein tyrosine
kinases in late preconditioning against myocardial stunning in
conscious rabbits. Circ Res. 1999;85:1154–1163.
19. Baines CP, Wang L, Cohen MV, Downey JM. Protein tyrosine kinase is downstream of protein kinase C for ischemic preconditioning’s anti-infarct effect in the rabbit heart. J Mol Cell Cardiol. 1998;30:383–392.[Medline] [Order article via Infotrieve]
20.
Ping P, Zhang J, Zheng YT, Li RCX, Dawn B, Tang XL,
Takano H, Balafanova Z, Bolli R. Demonstration of selective protein
kinase C–dependent activation of Src and Lck tyrosine kinases during
ischemic preconditioning in conscious rabbits. Circ
Res. 1999;85:542–550.
21. Sasaki N, Sato T, Ohler A, O’Rourke B, Marbán E. Activation of mitochondrial ATP-dependent potassium channels by nitric oxide. Circulation. In press.
22.
Holmuhamedov EL, Jovanovic S, Dzeja PP, Jovanovic A,
Terzic A. Mitochondrial ATP-sensitive K+ channels
modulate cardiac mitochondrial function. Am J Physiol. 1998;275:H1567–H1576.
23.
Piot CA, Padmanaban D, Ursell PC, Sievers RE, Wolfe CL.
Ischemic preconditioning decreases apoptosis in rat
hearts in vivo. Circulation. 1997;96:1598–1604.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||