Activation of Mitochondrial K
            <sub>ATP</sub>
            Channel Elicits Late Preconditioning Against Myocardial Infarction via Protein Kinase C Signaling Pathway

Takashi, En; Wang, Yigang; Ashraf, Muhammad

doi:10.1161/01.res.85.12.1146

Cited by 146 publications

(107 citation statements)

References 36 publications

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“…Takashi el al 11 showed that administration of diazoxide, 24 hours before prolonged ischemia, protected hearts from damage. This protection was abrogated by simultaneous administration of 5-HD on day 1.…”

Section: Resultsmentioning

confidence: 99%

Sarcolemmal K _ATP Channel Triggers Opioid-Induced Delayed Cardioprotection in the Rat

Patel

Hsu

Peart

et al. 2002

Circulation Research

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Recently, the involvement of sarcolemmal K ATP (sarcK ATP ) channels in ischemic and pharmacological preconditioning (IPC and PPC) has been minimized by numerous studies suggesting a primary role for mitochondrial K ATP (mitoK ATP ) channels in early and delayed cardioprotection. Although the mitoK ATP channel has clearly been shown to be a distal effector of delayed IPC and PPC, studies implicating it as a trigger of protection in delayed IPC are lacking. Accordingly, we characterized the role of cardiac K ATP channels as triggers or distal effectors of delayed cardioprotection induced by opioids in rats, and the data suggest that the sarcK ATP channel triggers and that the mitoK ATP channel is a distal effector of opioid-induced delayed cardioprotection. P rotection from myocardial infarction via ischemic preconditioning (IPC) has been described to be a biphasic event. The early phase occurs immediately after IPC and lasts 1 to 3 hours 1 ; the late phase of protection is seen 12 to 24 hours after the initial stimulus and lasts up to 72 hours. 2,3 We have previously shown that ␦ opioid agonists induce a delayed cardioprotective effect that appears to be mediated by a burst of reactive oxygen species (ROS). 4 In recent investigations, the mitochondrial ATP-dependent K ϩ (mitoK ATP ) channel has received considerable attention as being the trigger of early IPC. Studies in the isolated rabbit heart 5 and in isolated myocytes 6,7 have suggested that this channel contributes to protective signals via a redox-sensitive mechanism. 8,9 Similarly, data suggest that the mitoK ATP channel could be either a trigger that induces the expression of proteins or a distal effector in delayed IPC. However, little information is available on the triggering role of the sarcolemmal K ATP (sarcK ATP ) channel in delayed IPC.Therefore, we investigated the role of the sarcK ATP channel as a trigger or distal effector of delayed cardioprotection induced by ␦ opioid agonists. We present evidence suggesting that the sarcK ATP channel functions as the trigger and the mitoK ATP channel as a distal effector in opioid-induced delayed PC. Materials and MethodsThis study was performed in accordance with the guidelines of the Animal Care Committee of the Medical College of Wisconsin, which is accredited by the American Association of Laboratory Animal Care. Study Groups and Experimental ProtocolsMale Sprague-Dawley rats (250 to 300 g) were obtained from Charles River Laboratories, Wilmington, Mass, and randomly divided into groups and subjected to pretreatment with SNC-121 (0.1 mg/kg, IV), a ␦ opioid agonist, followed by a 24-hour recovery period. Selective and nonselective K ATP channel blockers were administered intravenously either with opioid pretreatment or after the recovery period just before index ischemia. All rats underwent 30 minutes of index ischemia followed by 2 hours of reperfusion. General Surgical Procedure and Infarct DeterminationGeneral surgical procedures and infarct determination were performed as described previously. 4 Br...

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Section: Resultsmentioning

confidence: 99%

Sarcolemmal K _ATP Channel Triggers Opioid-Induced Delayed Cardioprotection in the Rat

Patel

Hsu

Peart

et al. 2002

Circulation Research

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“…PKC inhibition before activation of mitoK ATP channels by DZX resulted in the loss of protection against ischemic injury in the rat myocardium. 1,17 Thus, it appears that PKC-catalyzed phosphorylation of K ATP channels is vital in preconditioning-induced protection.…”

Section: Discussionmentioning

confidence: 99%

“…It is well established that DZX selectively opens mitoK ATP channels 1,2,7 and is responsible for both early and late preconditioning. 1,17,20 Activation of mitoK ATP channels retards calcium accumulation by the mitochondria and either preserves ATP 1,4 or increases ATP synthesis. 21 Szewczyk 22 pointed out that the opening of mitoK ATP channels partially compensates the membrane potential, thereby enabling additional protons to be pumped out to form a substantial proton electrochemical gradient for both ATP synthesis and Ca 2ϩ transport.…”

Section: Discussionmentioning

confidence: 99%

“…31 Translocation of PKC isoforms to the nucleus may have implications for late preconditioning induced by DZX treatment. 17 It is still a matter of debate which PKC isoform mediates the effect of preconditioning. To further implicate that downregulation of PKC is responsible for the loss of protection, DZX was unable to open the channels in PKC-downregulated hearts, as evidenced by the extent of cell injury.…”

Section: Discussionmentioning

confidence: 99%

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Downregulation of Protein Kinase C Inhibits Activation of Mitochondrial K _ATP Channels by Diazoxide

Wang

Takashi

et al. 2001

Circulation

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Background-The mitochondrial K ATP (mitoK ATP ) channel has been shown to confer short-and long-term cardioprotection against prolonged ischemia via protein kinase C (PKC) signaling pathways. However, the exact association between PKC or its isoforms and mitoK ATP channels has not yet been clarified. The present study tested the hypothesis that the activity and translocation of PKC to the mitochondria are important for cardiac protection elicited by mitoK ATP channels. Methods and Results-PKC was downregulated by prolonged (24-hour) treatment with phorbol 12-myristate 13-acetate (4 g/kg body weight) before subsequent experiments in rats. Langendorff-perfused rat hearts were subjected to 40 minutes of ischemia followed by 30 minutes of reperfusion. Effects of PKC downregulation on the activation of mitoK ATP channels and other interventions on hemodynamic, biochemical, and pathological changes were assessed. Subcellular localization of PKC isoforms by Western blot analysis and immunocytochemistry demonstrated that PKC-␣ and PKC-␦ were translocated to the sarcolemma and that PKC-␦ was translocated to the mitochondria after diazoxide treatment. In hearts treated with diazoxide (80 mol/L), a significant improvement in cardiac function and an attenuation of cell injury were observed. In PKC-downregulated hearts, protection was abolished because mitoK ATP channels could not be activated by diazoxide. Conclusions-These data suggest that PKC activation is required for the opening of mitoK ATP channels during protection against ischemia and that this effect is linked to isoform-specific translocation of PKC-␦ to the mitochondria.

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“…Takashi et al [86] showed that diazoxide pretreatment decreased markers of apoptosis from ischemia/reperfusion injury, and that this effect was reversed by 5-HD. Akao et al [87] recently showed that diazoxide inhibits H 2 O 2 -induced apoptosis in neonatal rat cardiac myocytes, and that 5-HD blocks this effect.…”

Section: Mitok Atp and Apoptosismentioning

confidence: 99%

Mitochondrial K channels in cell survival and death

Ardehali¹,

O’Rourke²

2005

Journal of Molecular and Cellular Cardiology

196

151

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Since the discovery of the mitochondrial ATP-sensitive potassium channel (mitoK ATP ) more than 13 years ago, it has been implicated in the processes of ischemic preconditioning (IPC), apoptosis and mitochondrial matrix swelling. Different approaches have been employed to characterize the pharmacological profile of the channel, and these studies strongly suggest that cellular protection well correlates with the opening of mitoK ATP . However, there are many questions regarding mitoK ATP that remain to be answered. These include the very existence of mitoK ATP itself, its degree of importance in the process of IPC, its response to different pharmacological agents, and how its activation leads to the process of IPC and protection against cell death. Recent findings suggest that mitoK ATP may be a complex of multiple mitochondrial proteins, including some which have been suggested to be components of the mitochondrial permeability transition pore. However, the identity of the pore-forming unit of the channel and the details of the interactions between these proteins remain unclear. In this review, we attempt to highlight the recent advances in the physiological role of mitoK ATP and discuss the controversies and unanswered questions.

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Activation of Mitochondrial K _ATP Channel Elicits Late Preconditioning Against Myocardial Infarction via Protein Kinase C Signaling Pathway

Cited by 146 publications

References 36 publications

Sarcolemmal K _ATP Channel Triggers Opioid-Induced Delayed Cardioprotection in the Rat

Sarcolemmal K _ATP Channel Triggers Opioid-Induced Delayed Cardioprotection in the Rat

Downregulation of Protein Kinase C Inhibits Activation of Mitochondrial K _ATP Channels by Diazoxide

Mitochondrial K channels in cell survival and death

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Activation of Mitochondrial K ATP Channel Elicits Late Preconditioning Against Myocardial Infarction via Protein Kinase C Signaling Pathway

Cited by 146 publications

References 36 publications

Sarcolemmal K ATP Channel Triggers Opioid-Induced Delayed Cardioprotection in the Rat

Sarcolemmal K ATP Channel Triggers Opioid-Induced Delayed Cardioprotection in the Rat

Downregulation of Protein Kinase C Inhibits Activation of Mitochondrial K ATP Channels by Diazoxide

Mitochondrial K channels in cell survival and death

Contact Info

Product

Resources

About

Activation of Mitochondrial K _ATP Channel Elicits Late Preconditioning Against Myocardial Infarction via Protein Kinase C Signaling Pathway

Sarcolemmal K _ATP Channel Triggers Opioid-Induced Delayed Cardioprotection in the Rat

Sarcolemmal K _ATP Channel Triggers Opioid-Induced Delayed Cardioprotection in the Rat

Downregulation of Protein Kinase C Inhibits Activation of Mitochondrial K _ATP Channels by Diazoxide