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INVITED REVIEWS
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
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ABSTRACT |
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 TOP ABSTRACT Evidence Supporting Involvement...Signaling Pathways by Which...Evidence for Involvement of...Mechanisms by Which MitoKATP...Evidence for Involvement of...REFERENCES |
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ischemia; electron transport chain
Structurally, KATP channels are composed of two distinct proteins, an inwardly rectifying potassium channel (Kir) pore subunit and the sulfonylurea receptor (SUR), which may have a regulatory role as well as a function in modulating the sensitivity of the channel to ATP, other nucleotides, and pharmacological agonists or antagonists (69). It is currently known that the cardiac sarcolemmal KATP channel is composed of an octomeric complex of two types of subunits, the Kir6.2 and the SUR2A subunit. There is also evidence to suggest that there are two KATP channels in the cell, a sarcolemmal channel (sarcKATP channel) in which the structure has been clearly delineated and a putative channel in the inner mitochondrial membrane (mitoKATP channel). The mitoKATP channel has been characterized pharmacologically in cells and in isolated lipid bilayers; however, it has not been cloned and its molecular structure remains unknown. In fact, its very existence has been questioned in several recent publications (8, 29) and is currently an area of considerable controversy.
IPC is a phenomenon whereby brief intervals of sublethal ischemia either delay or reduce the extent of necrosis following a subsequent more prolonged episode of ischemia (23). IPC has two distinct phases, an early phase that lasts for 1–3 h following the IPC stimulus and a delayed phase (or second window) of protection that reappears at 18–24 h and persists for 24–72 h. The signaling pathways underlying the two forms of protection most likely share common elements, but the former is thought to primarily involve posttranslational modifications, whereas the latter also involves changes in gene expression and amounts of cardioprotective proteins. The signaling cascade triggered by IPC is still under debate, and there is evidence that the pathways involved in the protection mediated by acute IPC may depend on the stimulus used to elicit IPC and the end point of injury used to demonstrate the protective effect, i.e., infarct size, stunning, and arrhythmias (2). Infarct size reduction has been considered the gold standard when studying the efficacy of a preconditioning stimulus to protect the heart and is always attenuated following IPC. On the other hand, myocardial stunning is most likely not a good index of the efficacy of acute IPC, although it appears to be a more reliable indicator of IPC when studying the second window of protection, particularly in conscious animal models. Protection of IPC against arrhythmias is somewhat controversial and is very species dependent. A variety of "triggers" have also been identified that are activated and/or released during the preconditioning stimulus, including adenosine, catecholamines, bradykinin, opioids, and nitric oxide (NO) (49). These triggers may be species dependent and also dependent on the severity and length of the preconditioning stimulus (15). As an example, Schulz et al. (51) found that bradykinin was the dominant trigger released during a less severe preconditioning stimulus, whereas adenosine was only released during a more intense preconditioning stimulus. In rabbits, opioids, adenosine, and bradykinin all seem to play an equal triggering role. Regardless of these triggers, a number of mediators of IPC have been identified. Recent studies have implicated different protein kinases in the signaling cascade responsible for IPC, including Src tyrosine kinases, protein kinase C (PKC), phosphatidylinositol-3 kinase, p38 mitogen-activated protein kinase (MAPK), and the JAK/STAT pathway (2). In recent years, much research has focused on the central involvement of the sarcKATP or mitoKATP channel as both a trigger and distal effector in IPC with equivocal results (26, 49).
Although considerable evidence supporting a role for the KATP channel in acute IPC has been obtained, recent studies suggest that the KATP channel is also intimately involved as either a trigger or end effector in delayed IPC. Therefore, the central theme of this review will be to discuss the evidence for the involvement of the sarcKATP versus the mitoKATP channel or a mitochondrial site of action in both early and late IPC and potential mechanisms responsible for the cardioprotection observed. In addition, we will review recent evidence that supports the possibility of alternate sites of action of IPC and KATP channel openers within the mitochondria.
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Evidence Supporting Involvement of SarcKATP Channel in IPC |
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TOPABSTRACTEvidence Supporting Involvement...Signaling Pathways by Which...Evidence for Involvement of...Mechanisms by Which MitoKATP...Evidence for Involvement of...REFERENCES |
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Additional evidence supporting a protective role for the sarcKATP channel has been provided by using KATP-deficient COS-7 cells. By cotransfection of Kir6.2/SUR2A genes, Jovanovic et al. (23) demonstrated that delivery of Kir6.2 and SUR2A genes into COS-7 cells resulted in a K+ current in the presence of pinacidil. Furthermore, after cotransfection and treatment with pinacidil, the cells became resistant to hypoxia-reoxygenation as a result of inhibition of intracellular Ca2+ loading (23, 24). Given that COS-7 cells are noncontracting, these data provide further credence to the hypothesis that sarcKATP channels may provide cardioprotection independent of APD shortening. A recent study by Suzuki et al. (55) reported a failure of IPC to reduce infarct size in Kir6.2-deficient mice. However, as noted by these authors (55), the relative importance of the sarcKATP channel may have been exaggerated due to the rapid heart rate in the murine model. Neverthless, these results were supported by those of Rajashree et al. (44) who also demonstrated that transgenic mice expressing a mutant Kir6.2 subunit, with a reduced ATP sensitivity, were insensitive to IPC. However, the study of Rajashree et al. (44) performed in isolated hearts, used the measurement of postischemic contractile dysfunction as the end point of ischemic injury rather than infarct size. Because there is not always a good correlation between the extent of stunning and infarct size in isolated hearts (22), it is possible that these investigators may have missed a reduction in infarct size in these mutant mice subjected to IPC.
Although recent results demonstrate that the sarc-KATP channel
may trigger IPC, at least in mice, recent preliminary results obtained in the
authors' laboratory demonstrated that the sarcKATP channel is the
trigger for delayed IPC (see Fig.
1) in rats. In these studies, cardioprotection was induced by an
IPC protocol consisting of three 5-min cycles of ischemia interspersed with 5
min of reperfusion, 24 h before the more sustained ischemic insult. The
cardioprotective effect observed was blocked by HMR-1098 during the trigger
phase rather than during the mediator phase (unpublished results).
Furthermore, the results were duplicated by a 24-h pretreatment with SNC-121,
a selective 
-opioid receptor agonist
(42). Treatment with SNC-121
accelerated APD shortening, and its effect to reduce infarct size and APD
shortening was abolished by HMR-1098.
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Signaling Pathways by Which SarcKATP Channel May Trigger Acute IPC |
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TOPABSTRACTEvidence Supporting Involvement...Signaling Pathways by Which...Evidence for Involvement of...Mechanisms by Which MitoKATP...Evidence for Involvement of...REFERENCES |
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PKC has been well established as a major signaling intermediate in IPC. SarcKATP channels have been previously shown to be activated by PKC. Indeed, a recent study by Light et al. (28) demonstrated a functional coupling of PKC to the sarcKATP channel in mediating cardioprotection, and there is evidence that suggests that PKC activation/translocation may be upstream of KATP channel activation.
IPC has been shown to lessen the inhibition of sarcolemmal Na-K-ATPase activity, which normally occurs in the acute phase of ischemia and increases Na+/Ca+ exchange (34). Haruna et al. (19) reported that the infarct-limiting effect of IPC may be modulated via an interaction between Na-K-ATPase and sarcKATP channels. In this study, the infarct-limiting effect of IPC in anesthetized rabbits was abolished by digoxin, an inhibitor of Na-K-ATPase (19). By inhibiting Na-K-ATPase, digoxin increased the amount of subsarcolemmal ATP, which prevented the opening of the sarcKATP channel during IPC. However, digoxin did not alter the protective effect of the KATP opener cromakalim, because KATP channel openers would be expected to act directly on the channel, thus, having effects independent of intracellular ATP concentrations. Furthermore, diazoxide, a selective mitoKATP channel opener, failed to reduce infarct size when administered at a similar or 10-fold higher dose than that needed for cromakalim to produce its infarct-limiting effects (19). This finding is puzzling, however, because Garlid et al. (12) demonstrated that cromakalim and diazoxide had a similar degree of potency for opening mitoKATP in reconstituted mitochondria in lipid bilayers and elicited a similar degree of cardioprotection against stunning following ischemia-reperfusion in the isolated rat heart. The lack of protection afforded by diazoxide at a dose that would be expected to elicit cardioprotection via opening of the mitoKATP channel is surprising and suggests that the sarcKATP channel is intimately involved in the cardioprotective effects of IPC in this particular model.
Another possible mechanism by which opening of sarcKATP channels confers cardioprotection may be the result of a channel-induced change in a specific intracellular signaling pathway. Hyperpolarization following the activation of the sarcKATP channel may lead to activation of the mitoKATP channel. Waring and colleagues (65) demonstrated that hyperpolarization of rat hippocampal slices increases phospholipase D activity. Phospholiase D has been implicated in IPC (58), and diacylglycerol produced by phospholipase D has been demonstrated to activate and translocate PKC, which has been suggested to potentiate the opening of the sarcKATP and/or mitoKATP channel.
Although it seems possible that activation of the sarcKATP channel may lead to opening of the mitoKATP channel via cross talk or vice versa there is no direct evidence to support this hypothesis, and there have been a number of recent papers that have presented different roles for the sarcKATP and mitoKATP channel in IPC and cardioprotection. In a model of chronic hypoxia, where rabbits were raised from birth in either a normoxic or hypoxic environment, Kong and colleagues (26) demonstrated that either 5-HD, a selective mitoKATP antagonist, or HMR-1098, a putative selective sarcKATP antagonist, failed to completely abolish the protection afforded by chronic hypoxia and that only the combination of 5-HD and HMR-1098 was successful in completely abolishing the protective effects of chronic hypoxia. Furthermore, a recent paper by Sanada et al. (47) demonstrated that glibenclamide, a nonselective KATP channel blocker, completely abolished the protective effects of IPC, whereas 5-HD, a mitochondrial selective blocker, only partially blunted the infarct size-reducing effect in dogs. In a model of adenosine-enhanced IPC, Toyoda et al. (59) presented a temporal involvement of both sarcKATP and mitoKATP channels. These investigators indicated that the infarct size-reducing effects of adenosine-enhanced preconditioning are mediated by mitoKATP channels during ischemia, whereas sarcKATP channels modulate functional recovery during both ischemia and reperfusion. This concept is also supported by Light et al. (28), who reported that the protective effects of phorbol 12-myristate 13-acetate (PMA), a PKC activator, were partially inhibited by 5-HD during chemically induced hypoxia but not at reoxygenation, whereas HMR-1098, acting in a PKC and adenosine-dependent manner, was only effective in abolishing protection and the reduction in intracellular Ca2+ overload during reoxygenation. In contrast, recent work of Downey and Cohen's group (39) suggest that adenosine may signal independently of the KATP channel and act directly via a kinase pathway. Taken together, these data suggest that the sarcKATP and mitoKATP channels are independently involved in producing ischemic tolerance provided by IPC and may produce additive effects resulting in cardioprotection. Of course, a caveat in many of these studies is related to the selectivity of the pharmacological agents used as selective blockers of the sarcKATP and mitoKATP channels 5-HD and HMR-1098. There are studies to suggest that both of these so-called selective agents may have effects unrelated to KATP channel blockade or lack selectivity for the channel in question (29).
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Evidence for Involvement of MitoKATP channel in Acute IPC |
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TOPABSTRACTEvidence Supporting Involvement...Signaling Pathways by Which...Evidence for Involvement of...Mechanisms by Which MitoKATP...Evidence for Involvement of...REFERENCES |
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The first report that suggested that an enhanced shortening of the APD as a result of sarcKATP channel activation was not the mechanism responsible for cardioprotection provided by KATP openers was published by Yao and Gross in 1994 (68). This study demonstrated that a low dose of the nonselective KATP channel opener bimakalim, which did not effect APD shortening, still produced a cardioprotective effect comparable to that of two higher doses of bimakalim, which produced a significant shortening of APD. It was hypothesized that an intracellular site of action may have been responsible for the efficacy of bimakalim to reduce infarct size independent of APD shortening. Moreover, Grover et al. (17) added further weight to this hypothesis when they described a lack of correlation between APD shortening and cardioprotection following cromakalim and the protective effects of IPC were not attenuated by dofetilide, a class III antiarrhythmic, which prevented APD shortening in preconditioned hearts (16). Evidence for a role of KATP channel activation mediating the protective effects of IPC and KATP openers in the absence of a ventricular action potential has also been provided from studies in isolated non-beating cardiac myocytes (1). These data all suggested that the sarcKATP channel may not be totally accountable for the protective effects afforded by KATP openers and IPC and suggested a possible intracellular site of action.
Garlid et al. (12) provided the first direct evidence to support a role for the mitoKATP channel in cardioprotection. Utilizing reconstituted bovine heart mitochondria, these investigators found that diazoxide opened mitoKATP with a concentration of drug to produce a 50% increase in KATP channel opening in lipid bilayers of 0.8 µmol/l, whereas 800 µmol/l was required by diazoxide to open the sarcKATP channel. Furthermore, diazoxide, at concentrations that did not activate the sarcKATP channel, produced a pronounced cardioprotective effect comparable to that of cromakalim at similar doses, as evidenced by an increase in time to ischemic contracture and enhanced functional recovery following global ischemia and reperfusion in isolated rat hearts. The effects of diazoxide and cromakalim were abolished by the KATP channel antagonists 5-HD and glibenclamide, suggesting that mitoKATP channels may be responsible for these effects. In a more recent paper, Sasaki et al. (48) identified a novel pharmacological agent, MCC-134, which opens sarcKATP channels and blocks mitoKATP channels in the same molecule. In rabbit ventricular myocytes, MCC-134 blocked diazoxide-induced flavoprotein oxidation and activated sarcKATP channels. Similar results were also observed in mouse ventricular myocytes, and MCC-134 attenuated the effects of IPC in a rabbit myocyte model and in intact mouse hearts. All of these results are consistent with a primary role for the mitoKATP channel or a mitochondrial site of action in IPC and diazoxide-induced cardioprotection and a lesser role for the sarcKATP channel. In contrast, in one of the few studies performed in a large animal species, Schwartz et al. (53) was not able to block IPC in swine hearts subjected to multiple preconditioning cycles with 5-HD pretreatment. f
Whereas it is generally accepted that the mitoKATP channel, or at least a mitochondrial site of action, is involved in the cardioprotection afforded by IPC and diazoxide, it is still unclear as to whether its role is as a trigger or distal effector or both. Indeed, several reports support an involvement for the mitoKATP channel as both a trigger and end effector of IPC and KATP openers such as diazoxide (15, 49).
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Mechanisms by Which MitoKATP Channels Serve as a Trigger or Distal Effector of IPC |
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TOPABSTRACTEvidence Supporting Involvement...Signaling Pathways by Which...Evidence for Involvement of...Mechanisms by Which MitoKATP...Evidence for Involvement of...REFERENCES |
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-mediated pathway
(71).
Activation and translocation of specific PKC isoforms, regardless of
initiator (adenosine, etc.) appears to be central to opening of
mitoKATP channels, and indeed, these two phenomena may be
codependent. Gaudette et al.
(13) demonstrated in a sheep
model that protection provided by direct KATP openers could be
abolished by PKC antagonists and that protection mediated via activation of
PKC could be abrogated by KATP channel antagonists, implying that
activation of PKC and KATP channels are both codependent and
necessary for protection in the in vivo heart. Although these data are
intriguing, much research has placed PKC- upstream of
mitoKATP channel activation. Studying embryonic chick ventricular
myocytes, Liang (27)
demonstrated that PKC activation with PMA was effective in preconditioning the
myocyte, a response abolished by chelerythrine or calphostin C. Furthermore,
pretreatment with either glibenclamide or 5-HD attenuated PMA-induced
preconditioning, suggesting that the KATP channel was a downstream
effector of PKC-mediated preconditioning. In isolated rabbit hearts, Ohnuma et
al. (38) demonstrated that IPC
leads to a dramatic elevation in PKC-. Pretreatment with 5-HD abolished
the protective effects of IPC without altering changes in PKC-
activation. In addition, whereas infusion of diazoxide leads to a marked
reduction in infarct size, diazoxide treatment failed to translocate
PKC- or accelerate its translocation. More recently, Nozawa et al.
(36) showed that IPC in rats
produced a translocation of both PKC- and PKC-; however, 5-HD
blocked the effect of IPC without blocking the translocation of the two PKC
isoforms. These results suggest that the mito KATP channel or site
of action of 5-HD is distal to PKC.
In contrast, a recent study by Liu et al.
(31) demonstrated that
PKC- was downstream from mitoKATP activation in
apoptosis-limiting effects of IPC. Using ventricular myocytes from chick
embryos, Liu and colleagues
(31) reported that both IPC
and diazoxide treatment reduced apoptosis in cardiac myocytes and that both of
these effects were abolished by pretreatment with specific PKC inhibitors. In
addition, both IPC and diazoxide treatment activated PKC- in the
particulate fraction. These results were also supported by the data provided
by Wang and Ashraf (63) who
demonstrated a marked reduction in contractile function in hearts treated with
both chelerythrine and diazoxide (possibly via a
Ca2+-dependent mechanism) and that pretreatment with
diazoxide did indeed mediate translocation of specific PKC isoforms.
Diazoxide also induces early and late preconditioning via a NO-dependent pathway. In an in vivo rabbit heart model, Ockaili et al. (37) demonstrated that diazoxide treatment induces both early and late preconditioning, an effect blocked by administration of 5-HD, confirming that the anti-ischemic effect was due to opening of mitoKATP channels. Interestingly, the diazoxide-mediated protection was also abolished by NG-nitro-L-arginine methyl ester, an inhibitor of NOS, suggesting a dependency on NO. NO has also been shown to modulate the sensitivity of the KATP channel to intracellular ATP (54). Furthermore, NO has been demonstrated to activate certain PKC isoforms (43, 70).
The general assumption given to mitoKATP activation is that during transient ischemia a preconditioned state is triggered via various mechanisms. These "triggers" then lead to activation/translocation of PKC and other downstream kinases (p38MAPK, JUNK, and ERK1/2). MitoKATP channels are then subsequently phosphorylated and opened earlier to provide protection via unknown mechanisms during the sustained ischemic insult. A recent study by Carroll and Yellon (6) described that delayed protection in a cardiomyocyte-derived cell line involves p38 MAPK and the opening of mitoKATP channels. In this model, the protective effects of IPC were abolished when cells were pretreated with SB-203580, a p38 MAPK inhibitor, before the preconditioning stimuli. Furthermore, protection was attenuated when cells were treated with 5-HD 30 min before lethal simulated ischemia on the second day following preconditioning. These results suggest that mitoKATP channel opening is downstream from p38 MAPK activation (6). However, another study places MAPK activation downstream from mitoKATP channel opening. Using THP-1 cells, Samavati et al. (46) demonstrated that diazoxide induces mitochondrial reactive oxygen species (ROS) production, as evidenced by an increased rate of dihydroethidium and dichlorofluorescein flouresence. Moreover, the increase in ROS resulted in an increase in the phosphorylation of ERK, a member of the MAPK family. Thus, opening of mitoKATP channels was associated with the downstream activation of ERK. The results of Wang and Ashraf (63), Samavati et al. (46), and Liu et al. (31) suggest that mitoKATP activation may also act as a trigger of cardioprotection. In agreement, Pain et al. (41) demonstrated that in isolated rabbit hearts, protection afforded by diazoxide could only be abolished when KATP channel blockers were given during diazoxide treatment, not after treatment. Furthermore, free radical scavengers given during the trigger phase also abolished the protective effects of diazoxide (10). Diazoxide has been previously shown to mediate cardioprotection in cells via a redox-sensitive mechanism whereby it initiates a burst of free radicals (5, 10), a known trigger leading to a preconditioned state, possibly through activation of specific kinases. Vanden Hoek et al. (60) presented evidence in isolated chick myocytes that a brief period of hypoxia generated ROS, which triggered a preconditioning-like response and attenuated a more marked release of ROS following a more prolonged period of ischemia and reoxygenation (61). They also found that PKC and the mitoKATP channel appeared to be an important part of the trigger phase of this response (60).
The answer to the question "is the mitoKATP channel the trigger or the mediator of IPC?" may be quite simple indeed, it may be both. A study by Wang et al. (64) examined the mitoKATP channel as both a trigger and a mediator. In an isolated rabbit heart model, the protective effects of diazoxide pretreatment (with a washout period) were eliminated by coadministration of either 5-HD, the L-type Ca2+ channel blocker nifedipine or by the PKC inhibitor chelerythrine. In contrast, when given following diazoxide treatment, chelerythrine was unsuccessful and 5-HD was only able to block the protection at a fourfold higher dose. Thus it was proposed that the trigger phase may be mediated by the elevation of intracellular Ca2+ and PKC activation, whereas mitoKATP opening invokes protection during the mediator phase via unknown mechanisms, which are independent of PKC activation/translocation. Thus there is considerable evidence that the mitoKATP may have a role as a trigger and/or distal effector in IPC-mediated cardioprotection. However, recently Schulz et al. (50) presented data in anesthetized pigs to suggest that the KATP channel only served a trigger role in this species because glibenclamide only blocked IPC when given before the brief ischemic stimulus and not 10 min after IPC. This study did not use 5-HD to determine whether the mitoKATP or sarcKATP channel was involved in the trigger phase (50).
It appears that the mitochondria have an intimate role in cell survival through maintaining or enhancing ATP synthesis and maintenance of Ca2+ homeostasis as well as regulation of mitochondrial volume. Ischemia-reperfusion impairs mitochondrial function through an alteration of membrane potential, imbalance of cytosolic ions, electron transport, and an increased production of free radicals. In an isolated cell model, anoxiareoxygenation may lead to a hyperpolarization of mitochondria. This hyperpolarization may indeed drive Ca2+ into the mitochondria, leading to Ca2+ overload. Xu and associates (66) demonstrated that treatment with diazoxide stabilized the mitochondrial membrane potential through limiting the decrease of membrane potential and by inhibition of the high polarization observed during anoxia-reoxygenation. Depolarization of the membrane potential may reduce Ca2+ influx, limiting Ca2+ overload and myocyte injury. Although having no effect on total intracellular Ca2+ levels, IPC has been shown to inhibit the ischemia-induced elevation of mitochondrial Ca2+ concentrations, an effect attributed to mitoKATP channel opening. Diazoxide reduced mitochondrial Ca2+ concentration and 5-HD inhibited the reduction in mitochondrial Ca2+ concentration provided by IPC and diazoxide in isolated rat hearts (63). The study by Xu and colleagues (66) reported that diazoxide treatment also prevented ATP depletion. In a model using arterially perfused guinea pig right ventricular walls, McPherson et al. (32) reported that KATP channel opening with pinacidil inhibited ischemia-induced depletion of high-energy phosphates. This pinacidil-induced preservation of creatine phosphate and ATP was abolished by glibenclamide pretreatment and glibenclamide alone enhanced the ischemia-induced depletion of ATP. MitoKATP channel opening may partially restore the membrane potential, allowing further extrusion of H+, forming a more favorable electrochemical gradient (56) for ATP synthesis. In this regard, diazoxide has recently been found to exert a unique protective action on mitochondrial membrane potential and membrane integrity (9). In cultured cardiac myocytes exposed to H2O2, diazoxide decreased the number of cells undergoing membrane depolarization and delayed the loss in membrane potential. In combination with cyclosporin A, diazoxide also exhibited an additive effect to inhibit the progression to cell death. These effects were selectively blocked by 5-HD, whereas other cardioprotective mechanisms, such as those produced by the adenine nucleotide translocase inhibitor bongkrekic acid were not blocked by 5-HD. Although not measured in this study, these effects would reduce ATP depletion, which will maintain ATP-dependent ion pumps such as the Na-K pump and Ca2+ pumps. Thus maintenance of ATP levels may further support Ca2+ homeostasis. Diazoxide increases the half-saturation constant for ADP stimulation of respiration and limits ATP hydrolysis, thus effectively preserving the adenine nucleotide pool during ischemia and the energy transfer during reperfusion (56). Recent studies by Garlid et al. (11), suggested that the reported changes in mitochondrial membrane potential and Ca2+ accumulation are merely "epiphenomena" produced by high concentrations of mitoKATP openers. Garlid et al. (11) hypothesized that the critical effect resulting from opening mitoKATP channels is in the regulation of mitochondrial matrix volume. Mitochondrial volume has been shown to regulate the electron transport chain and preserve the architecture of the intermembrane space, permitting a more efficient energy transfer between mitochondria and cellular ATPases. Indeed, opening of the mitoKATP channel may maintain the structure of the intermembrane space during ischemia, preserving the low permeability to ADP and ATP. In contrast, Lim et al. (29) and Das et al. (8) both recently suggested that changes in mitochondrial volume could not explain the beneficial effects produced by IPC and diazoxide treatment.
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Evidence for Involvement of Electron Transport Chain in IPC and Pharmacological PC |
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TOPABSTRACTEvidence Supporting Involvement...Signaling Pathways by Which...Evidence for Involvement of...Mechanisms by Which MitoKATP...Evidence for Involvement of...REFERENCES |
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In conclusion, recent data suggest that both the sarcKATP and mitoKATP channels play complimentary roles in the protection afforded by IPC. On the basis of recent evidence, activation of the mitoKATP channel appears to limit cell death, whereas opening of the sarcKATP channel appears to limit stunning. Regardless, direct activation of either the sarcKATP or mitoKATP channels provide significant cardioprotection, and the possible signaling pathways involved are schematically shown in Fig. 3. Activation, especially of the mitoKATP, may be involved in acute IPC as either a trigger and mediator, end effector, or both. Opening of the mitoKATP channel may result in a ROS "burst," which may in itself have a preconditioning effect. Translocation/activation of PKC and other kinases may lie both upstream and downstream of the mitoKATP channel, perhaps acting as a positive feedback to elicit a more robust opening of the channel. As a potential end effector, the role that opening of the mitoKATP plays in increasing mitochondrial cell volume may be intimately involved in the protective effects of both IPC and direct activation of the channel. Following that, the sarcKATP channel may indeed act as a trigger for the opening of the mitoKATP channel or confer its own cardioprotective effect via a PKC-dependent mechanism, which ultimately leads to a reduction in Ca2+ overload during ischemia. Moreover, Kir6.2-deficient mice are insensitive to IPC. Thus it appears that both the sarcKATP and mitoKATP have complimentary roles in the cardioprotection afforded by IPC and certain KATP openers, indeed, they may act together to elicit beneficial effects on the myocardium.
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTEvidence Supporting Involvement...Signaling Pathways by Which...Evidence for Involvement of...Mechanisms by Which MitoKATP...Evidence for Involvement of...REFERENCES |
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. Am J Physiol Heart
Circ Physiol 282:
H1380–H1386, 2002. activation in the
mechanism of preconditioning. Am J Physiol Heart Circ
Physiol 283:
H440–H447, 2002. in cardiomyocytes.
Am J Physiol Heart Circ Physiol
282: H1395–H1403,
2002.This article has been cited by other articles:
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  E. Murphy, R. Wong, and C. Steenbergen Signalosomes: delivering cardioprotective signals from GPCRs to mitochondria Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H920 - H922. [Full Text] [PDF]
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B. Zhong and D. H. Wang N-oleoyldopamine, a novel endogenous capsaicin-like lipid, protects the heart against ischemia-reperfusion injury via activation of TRPV1 Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H728 - H735. [Abstract] [Full Text] [PDF]
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J. D. O'Brien and S. E. Howlett Simulated ischemia-induced preconditioning of isolated ventricular myocytes from young adult and aged Fischer-344 rat hearts Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H768 - H777. [Abstract] [Full Text] [PDF]
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