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Departments of 1 Cell Biology and Neuroscience, 2 Physiology, and 3 Medicine, University of South Alabama, College of Medicine, Mobile, Alabama 36688
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The role of mitochondrial free radicals in the cardioprotective effect of ischemic preconditioning was examined in isolated buffer-perfused rat hearts. Infarct size in control rat hearts subjected to 30 min of regional ischemia and 120 min of reperfusion was 32.6 ± 3.4% of the risk zone. Ischemic preconditioning (3 cycles of 5-min global ischemia/5-min reperfusion) before the same regional ischemia and reperfusion protocol significantly reduced infarct size to 2.6 ± 0.8% of the risk zone. Perfusion with menadione (3.0 µM), a generator of mitochondrial free radicals, in lieu of preconditioning ischemia significantly reduced infarction to 10.9 ± 2.7%. N-2-mercaptopropionylglycine (1.0 mM), a free radical scavenger, blocked the protection of menadione, significantly increasing infarction to 23.5 ± 1.1%. Myxothiazol (0.6 µM), a site III mitochondrial inhibitor, blocked the protection of menadione and significantly increased infarction to 25.2 ± 3.8%. The infarct-limiting effect of menadione was attenuated to 19.7 ± 1.5% of the risk zone by 10 µM SB203580, a p38 mitogen-activated protein kinase (MAPK) inhibitor. Furthermore, menadione significantly increased p38 MAPK phosphorylation to a level 5.6-fold over basal. These results indicate that free radicals that originate within mitochondria can activate p38 MAPK and protect hearts against infarction.
myocardial infarction; ischemia; mitochondria; p38 MAPK
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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ISCHEMIC PRECONDITIONING (PC) is a protective process in which brief episodes of ischemia cause the heart to resist infarction during a subsequent ischemic insult (24). While a large body of evidence has shown that activation of protein kinase C (PKC) is a key step in cardioprotection, events downstream from PKC are not fully understood (8). The protection afforded by PC ischemia and by activation of PKC can be mimicked by the opening of mitochondrial ATP-sensitive potassium (KATP) channels. Diazoxide, a selective mitochondrial KATP channel opener, protects cardiomyocytes against simulated ischemia (13, 19), limits the size of infarction in rabbit hearts (3, 28), and improves ventricular function in rat hearts subjected to 30 min of ischemia (12). Moreover, 5-hydroxydecanoate, a selective mitochondrial KATP channel blocker, abolishes the protection caused by ischemic PC or by treatment with diazoxide (17, 28, 31). Interestingly, free radical scavengers also block the cardioprotective effect of ischemic PC (2) and diazoxide (12, 28). These results have established an important role for mitochondrial KATP channels in PC, but the mechanism of protection remains largely unknown.
We have shown that phosphorylation of the activation site of p38 mitogen-activated protein kinase (MAPK) was significantly increased in PC rabbit hearts in a time-dependent and specific manner during ischemia (37). Maulik et al. (22) observed that PC increased the activity of MAPK-activated protein kinase 2, a downstream substrate of p38 MAPK, in rat hearts, and we (3) reported similar findings in rabbit hearts. Furthermore, the protective effect of PC against infarction was mimicked by anisomycin, a p38 MAPK activator, in rabbit hearts (3). Our studies have shown that SB203580, a p38 MAPK inhibitor (9), blocked protection in PC and anisomycin-treated isolated rabbit cardiomyocytes (37). SB203580 also blocked the infarct-limiting effect of PC ischemia in rat (23) and rabbit hearts (27), and the protection afforded by PC against lethal ischemia was blocked by SB203580 in rat myoblast H9c2 cells (25). The role of p38 MAPK in PC is controversial, however, because SB203580, and the related compound SB202190, protected cells during ischemic stress (20, 33). The infarct-limiting effect of PC can be mimicked by free radical production (2), possibly by the activation of p38 MAPK (7, 34), but further studies are needed to elucidate the mechanism of this protection.
Clarification of the cascade of events that trigger the protection of PC clearly has important clinical implications. In this study, we examined whether the cardioprotection associated with p38 MAPK activation and the production of free radicals might be related. This issue was addressed by testing the effects of menadione, a compound that produces free radicals at site III within the inner mitochondrial membrane (11, 35). Rat hearts were perfused with menadione in lieu of PC ischemia, and the effects on infarction size and p38 MAPK activity were evaluated. These studies were repeated in the presence of N-mercaptopropionylglycine (MPG) to further examine the involvement of free radicals. The effects of menadione were then examined in the presence of the mitochondrial inhibitor myxothiazol and the p38 MAPK inhibitor SB203580. The data are consistent with a cellular cascade in which the production of mitochondrial free radicals causes the activation of p38 MAPK and protects the heart against infarction.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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All experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (Revised 1996).
Infarct size studies.
Male Wistar rats (285-310 g) were anesthetized with pentobarbital
sodium (60 mg/kg ip). As previously described (18), rat hearts were removed surgically and rapidly mounted on a Langendorff apparatus for perfusion with warmed (37°C) Krebs-Henseleit buffer [containing (in mM) 118.5 NaCl, 4.7 KCl, 1.2 MgSO4, 1.25 CaCl2, 24.8 NaHCO3, 1.2 KH2PO4, and 10 glucose], which was gassed with 95% O2-5% CO2. A latex balloon was placed in
the left ventricle to measure developed ventricular pressure. A 6-0 silk suture was placed around the left coronary artery to form a snare,
and the preparation was allowed to stabilize for 20 min. The protocols for all experimental groups are illustrated in Fig.
1. All hearts were subjected to 30 min of
regional ischemia followed by 120 min of reperfusion. The
ischemic PC protocol consisted of three cycles of 5 min of
global ischemia each followed by 5 min of reperfusion before
the onset of prolonged regional ischemia. Menadione (3.0 µM)
was added directly to the perfusion buffer, and hearts were treated for
20 min before regional ischemia. MPG (0.3-1.0 mM) was
added to the perfusion buffer 5 min before the menadione treatment, and
it was perfused until the onset of ischemia. Similarly,
myxothiazol (0.6 µM) and SB203580 (10 µM) were diluted from
DMSO stock solutions, added to the perfusion buffer 5 min before
menadione treatment, and perfused until prolonged ischemia. At
the conclusion of 120 min of reperfusion, the coronary artery was
reoccluded, and 1-10 µM zinc/cadmium sulfide particles were
infused to mark the nonfluorescent tissue as the risk zone. Hearts were
frozen, cut into slices (1 mm), and incubated in sodium phosphate
buffer containing 1% triphenyltetrazolium chloride for 15 min to
visualize the unstained infarcted region. Infarct and risk zone areas
were determined with planimetry, and infarct size was expressed as a
percentage of the risk zone. All compounds were purchased from Sigma
unless otherwise indicated.
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Western blotting for activated p38 MAPK. The activation state of p38 MAPK was evaluated using a phospho-specific antibody that recognizes p38 MAPK only if both activation sites (threonine 180 and tyrosine 182) are phosphorylated (9211S, New England Biolabs). Rat hearts were isolated as described above and divided into non-PC, PC, and menadione-treated hearts. The non-PC hearts experienced only 30 min of global ischemia. PC hearts received three cycles of 5-min global ischemia and 5-min reperfusion before 30 min of global ischemia. Menadione-treated hearts were perfused for 20 min with 3.0 µM menadione before 30 min of global ischemia. Left ventricular biopsies were obtained from the hearts after 30 min of stabilization (basal), before the onset of global ischemia, and at 10 and 20 min of global ischemia in PC and menadione-treated hearts. Biopsies were obtained from non-PC hearts before the onset of global ischemia and after 10 and 20 min.
Biopsy samples were frozen rapidly in liquid nitrogen and homogenized using methods previously reported (26). In brief, frozen pieces of rat heart were disrupted with a Polytron tissue homogenizer in ice-cold lysis buffer modified from Bogoyevitch et al. (6) (75 mM
-glycerol phosphate, 20 mM HEPES, 2 mM EGTA, 2 mM EDTA, 1 mM Na3VO4, 0.05% Triton X-100, 4 µg/ml leupeptin, and 1 mM phenylmethylsulfonyl fluoride; pH 7.2) and
centrifuged at 13,000 g at 4°C for 10 min. The protein
content of the cytosolic fractions was determined by Lowry assay
(500-0116, Bio-Rad), and 20-µg samples were loaded on 10%
SDS-polyacrylamide gels for electrophoretic separation. Proteins were
transferred to nitrocellulose membranes and probed with
phospho-specific p38 MAPK antibody (9211S, New England Biolabs). The
antibody-labeled proteins were visualized after a previously reported
(26) chemiluminescence detection method (Phototype-HRP,
New England Biolabs). The absorbance of the labeled protein bands was
digitally scanned and quantified by normalization to basal values.
Statistics. All data are presented as means ± SE. One-way ANOVA with Tukey's post hoc test was performed on infarct size and baseline hemodynamics, and an ANOVA with repeated measures was used to analyze the p38 MAPK phosphorylation data. Data were considered significant at the P < 0.05 level.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Hemodynamics.
There were no significant differences in basal heart rate, basal
developed pressure, or basal coronary flow between any of the
experimental groups (Table 1).
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Infarct size.
There were no significant differences in body weight, heart weight, or
the size of the risk zone between any of the experimental groups (Table
2). Figure
2 shows that infarct size was 32.6 ± 3.4% of the risk zone in control hearts (n = 7).
Hearts preconditioned with three cycles of 5-min ischemia had
significantly reduced infarct size, to 2.6 ± 0.8% of the risk
zone (n = 7). A robust protective effect was
observed in hearts perfused with 3.0 µM menadione for 20 min before
ischemia (infarction = 10.9 ± 2.7%, n = 6). This cardioprotective effect was not
significantly different from that produced by PC ischemia.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study is the first to demonstrate that menadione exerts a potent protective effect against infarction of the myocardium. Menadione produces free radicals within the mitochondrial inner membrane (11, 35). A growing body of evidence suggests that free radicals can act as second messengers in the heart (7, 10). Yao et al. (38) observed that free radicals produced by acetylcholine treatment protected isolated chick cardiomyocytes against simulated ischemia. This protection was dependent on mitochondrial KATP channels, and it was blocked by 1 mM MPG, a free radical scavenger. Free radical scavengers also block the infarct-limiting effect of mitochondrial KATP channel opening (12, 28) and PC ischemia (2). Therefore, we perfused menadione to test if the source of protective free radicals could be the mitochondria. Our experiments show that treatment with 3.0 µM menadione in lieu of PC ischemia significantly reduced infarction compared with control hearts. Interestingly, treatment of CCL39 cells with 100 µM menadione protected the cells against oxidative stress in a manner that involved activation of the p38 MAPK cascade (14, 15). In addition, menadione led to the activation of p38 MAPK in the rat heart (7) and H9c2 cardiac cells (34). Some studies have shown that higher doses of menadione can harm tissues, but no adverse effects were observed on ventricular function (~3 µM) in guinea pig hearts (11), and we did not observe infarction out of the risk zone in hearts treated with menadione.
The protection caused by menadione was dependent on the production of free radicals. This was demonstrated in hearts that were treated with MPG before menadione treatment. MPG (1.0 mM) blocked the protection of menadione, increasing infarction to 23.5 ± 1.1%. Lower doses of MPG (300 and 600 µM) failed to block the protection of menadione in our early studies. Protection by one cycle of PC was blocked by 300 µM MPG in rat and rabbit hearts (1, 2). Interestingly, however, this dose failed to block protection by four cycles of PC in rabbit hearts (2). MPG (1.0 mM) blocked free radical production induced by acetylcholine treatment in chick cardiomyocytes (38) and improved aortic function after hypoxia in rat hearts (39). It appears that free radical production during PC is stimulus dependent and a critical dose of MPG is needed to be effective. This may explain why free radical scavengers have failed to block ischemic PC in some prior studies (16, 30).
The protection afforded by menadione was blunted by 0.6 µM myxothiazol, an inhibitor of the site III complex in the electron transport chain (5, 7). This dose of myxothiazol blocked acetylcholine-mediated production of free radicals in chick cardiomyocytes (5). Moreover, the activation of p38 MAPK by hydrogen peroxide was blocked by 1.0 µM myxothiazol in isolated cardiomyocytes (7). We observed that the protection of menadione was blocked by 0.6 µM myxothiazol. Perfusion of myxothiazol alone slightly decreased infarction size, although not to the level of significance, possibly indicating an additional effect of this drug. Thus the data are consistent with a cardioprotective effect mediated by the production of free radicals within mitochondria.
To address the mechanism of this protection further, we examined the effect of menadione in the presence of SB203580. The protection of menadione was blunted by 10 µM SB203580, consistent with a protective mechanism involving the activation of p38 MAPK. Further evidence for a role of p38 MAPK in protection was observed in Western blot studies that showed that p38 MAPK was activated by 3.0 µM menadione. Three cycles of PC were more protective against infarction than treatment with menadione. This could suggest that PC activates additional protective pathways, whereas the effects of menadione are confined to a free radical-dependent pathway. Indeed, our recent data suggest that adenosine activates a second protective mechanism in isolated rabbit hearts (unpublished observations). Alternatively, this may reflect a dosing effect because three cycles of PC were used in our model. While these issues warrant further investigation, the data demonstrate that p38 MAPK must be activated to observe the protection of menadione during ischemia.
A number of studies have shown that activation of p38 MAPK can be detrimental to the ischemic heart. Inhibition of p38 MAPK by SB203580 caused a dose-dependent enhancement of cell viability and reduced levels of caspase-3 during prolonged lethal ischemia in studies using cultured neonatal rat cardiomyocytes (20, 32). Furthermore, SB202190, a related p38 MAPK inhibitor, enhanced recovery of ventricular function in globally ischemic rat hearts (33). It is not known why p38 MAPK activation is beneficial in some studies and harmful in others, but experimental differences warrant consideration. Our studies examined infarct size in whole hearts as the end point, whereas many prior investigations examined cell viability during simulated ischemia as the end point. One exception in the pig showed that the infarct size-limiting effect of PC was not blocked by SB203580 (4). However, the SB compound was locally infused into the center of the ischemic zone in that study, and the tissue concentration could not be controlled. Another contributing factor may be differences in the dynamics of cell death during simulated ischemia in cultured cardiomyocytes compared with the ischemia that develops in a beating heart (21). There is also evidence suggesting that isoforms of p38 MAPK are activated differentially to perform different functions in the heart during stress (29, 36).
In summary, this study is the first to report that the production of mitochondrial free radicals by menadione can protect hearts against infarction. The generation of these mitochondrial free radicals appears to be a fundamental step in cardioprotection because the latter was blocked by MPG. Moreover, cardioprotection was blocked by myxothiazol, establishing the electron transport chain in mitochondria as the source of protective free radicals. The activation of p38 MAPK by menadione and inhibition of the protection of menadione by SB203580 further indicate an important role for the activation of p38 MAPK in ischemic PC.
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ACKNOWLEDGEMENTS |
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This study was supported by American Heart Association Grant 980237 (to S. D. Critz) and National Heart, Lung, and Blood Institute Grants HL-20648 (to J. M. Downey) and HL-50688 (to M. V. Cohen).
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. D. Critz, MSB 2018, Dept. of Cell Biology and Neuroscience, Univ. of South Alabama, College of Medicine, Mobile, AL 36688 (E-mail: scritz{at}usamail.usouthal.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 27 November 2000; accepted in final form 21 March 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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L. G. Kevin, A. K. S. Camara, M. L. Riess, E. Novalija, and D. F. Stowe Ischemic preconditioning alters real-time measure of O2 radicals in intact hearts with ischemia and reperfusion Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H566 - H574. [Abstract] [Full Text] [PDF]
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R. M Smith, S. Lecour, and M. N Sack Innate immunity and cardiac preconditioning: a putative intrinsic cardioprotective program Cardiovasc Res, August 15, 2002; 55(3): 474 - 482. [Abstract] [Full Text] [PDF]
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 P. Eaton, H. L. Byers, N. Leeds, M. A. Ward, and M. J. Shattock Detection, Quantitation, Purification, and Identification of Cardiac Proteins S-Thiolated during Ischemia and Reperfusion J. Biol. Chem., March 15, 2002; 277(12): 9806 - 9811. [Abstract] [Full Text] [PDF]
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, Individual
experimental observations; 
, group means ± SE.
