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CARDIOVASCULAR
-Opioid Receptors
Department of Physiology, The University of Hong Kong, Hong Kong Special Administrative Region, China (C.-M.C., M.C., S.W., T.-M.W.); and Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China (Q.X., J.T.)
Received October 6, 2003; accepted January 26, 2004.
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Abstract |
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-opioid receptor (OR). The cardioprotective effect of IL-2 was evaluated by measuring infarct size and lactate dehydrogenase (LDH) release in response to ischemia and reperfusion in the isolated rat heart. IL-2 at an optimal dose of 50 U/ml mimicked the effect of ischemic preconditioning by reducing infarct size and LDH release. The infarct and LDH-reducing effects of IL-2 were blocked by nor-binaltorphimine (5 µM), a -OR antagonist, but not naltrindole (5 µM), a 
-OR antagonist known to block the action of its stimulation. Moreover, blockade of the mitochondrial ATP-sensitive potassium (mito-KATP) channel with a selective antagonist, 5-hydroxydecanoate (100 µM), or a nonselective antagonist of KATP channels, glybenclamide (100 µM), or blockade of protein kinase C (PKC) with its inhibitors chelerythrine (5 µM) or GF 109203X (10 µM) [3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride] abolished the protective effect of IL-2. Administration of free radical scavengers N-acetylcysteine (4 mM) or N-(2-mercaptopropionyl)-glycine (1 mM) also abolished the protective effects of IL-2 and U50,488H [(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide], a selective -OR agonist. This study provides the first evidence that IL-2 confers cardioprotection against injury induced by ischemia/reperfusion. The effect of IL-2 is mediated via -OR as evidenced by -OR antagonism and similar signaling mechanisms, mito-KATP, PKC, and reactive oxygen species involved in the cardioprotective effects of both IL-2 and -OR stimulation.
; Bolli, 2000; Nakano et al., 2000). This is called cardioprotection by ischemic preconditioning (IPC). Since the first demonstration of the phenomenon by Murry et al. (1986), intensive research has focused on the mechanism. It is now well known that IPC is mediated by numerous Gi protein-coupled receptors. The -opioid receptor (OR) has recently been shown to mediate both immediate (Wang et al., 2001a) and delayed (Wu et al., 1999) cardioprotection by preconditioning with ischemia or metabolic inhibition/anoxia. Blockade of either the mitochondrial ATP-sensitive potassium (mito-KATP) channel (Wang et al., 2001a) or protein kinase C (PKC) (Wang et al., 2001b) has been shown to abolish the effector of -OR stimulation, suggesting that both mito-KATP and PKC maybe involved in cardioprotection of -OR stimulation.
Recent evidence shows that interleukin 2 (IL-2), the most important member of the cytokine family and produced by activated helper T lymphocytes, produces a negative inotropic action in the isolated perfused rat heart, and this action is -OR-mediated (Cao et al., 2002). There is also evidence that the mRNA level of IL-2 increases in the ischemic myocardium of rats subjected to left anterior descending artery occlusion (Herskowitz et al., 1995). We therefore hypothesize that preconditioning with IL-2 may confer cardioprotection via the -OR.
Reactive oxygen species (ROS) have been implicated to be involved in cardioprotection of IPC (Baines et al., 1997; Tritto et al., 1997). It has also been shown that the release of ROS from mitochondria reduces infarction in isolated and buffer-perfused rat hearts (Yue et al., 2001), whereas free radical scavengers block the protection of IPC (Baines et al., 1997). Stimulation of 1-OR has been shown to cause mitochondria to release oxygen radicals in cardiomyocytes, an effect correlating with cardioprotection (McPherson and Yao, 2001a,b). Recent evidence suggests that these radicals activate PKC (Cohen et al., 2001) and mediate cardioprotection (Simkhovich et al., 1998). Whether ROS are involved in the cardioprotection of -OR stimulation is not known.
Therefore, the primary purpose of the present study was to test the hypothesis that pretreatment with IL-2 confers cardioprotection and that the effect is mediated via -OR. We first established the cardioprotective effects of preconditioning with IL-2 in an isolated perfused rat heart preparation. To determine the involvement of -OR, two approaches were used. The first was to determine the effect of IL-2 upon blockade of the -OR. Second, we compared the signaling mechanisms involved in cardioprotection of preconditioning with IL-2 and -OR stimulation with its agonist U50,488H (U50). The secondary signal transduction components we studied were the mito-KATP channel, PKC, and ROS. The results show that IL-2 confers cardioprotection via the -OR. In addition to mito-KATP channels and PKC, ROS may also be involved in cardioprotection of pretreatment with either IL-2 or U50,488H.
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Materials and Methods |
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A balloon was inserted through the left atrium into the left ventricle and the left ventricular end diastolic pressure (LVEDP) was adjusted between 4 and 8 mm Hg. Cardiac parameters were monitored continuously and included heart rate (HR), left ventricular developed pressure (LVDP: difference between left ventricular end systolic pressure and end diastolic pressure), the rate-pressure product (left ventricular developed pressure multiplied by the heart rate, LVDP x HR), the velocity of contraction and relaxation (±dP/dtmax). Coronary flow (CF) was measured by timed collection of effluent at regular intervals using a calibrated tube and expressed in milliliters per minute.
The Guide for Care and Use of Laboratory Animals as promulgated by the National Research Council was adopted. The protocol of this study was approved by the Committee on the Use of Experimental Animals for Teaching and Research, The University of Hong Kong.
Measurement of the Area of Risk. For determination of infarct size in hearts subjected to regional ischemia, the coronary artery was reoccluded at the end of the reperfusion period, and a solution of 2.5% Evans blue was perfused to delineate the area of risk. Hearts were then frozen and cut into slices, which were then incubated in sodium phosphate buffer containing 1% (w/v) 2,3,5-triphenyl-tetrazolium chloride for 15 min to visualize the unstained infarcted region. Infarct and risk zone areas were determined with planimetry using Image/J software from National Institutes of Health. Infarct was expressed as a percentage of the risk zone.
The mean values of the risk zones from different treatment groups ranged from 49.84 ± 2.08 to 61.90 ± 3.69. There was no significant difference among groups (data not shown).
Determination of Myocardial Injury via Enzyme Efflux. To assess the extent of myocardial injury, the effluent was collected at 5, 10, 30, 60, 90, and 120 min of reperfusion and lactate dehydrogenase (LDH) was spectrophotometrically assayed using a kit purchased from Sigma-Aldrich (St. Louis, MO). LDH activity was expressed as units per liter (Li et al., 1999).
Experimental Protocol. As shown in Fig. 1, all hearts were allowed to equilibrate for at least 15 min and were subsequently subjected to a standard 30 min of regional ischemia followed by 120 min of reperfusion. Ischemic preconditioning was elicited by two cycles of 5 min of ischemia followed by 5 min reperfusion before standard ischemia. Similar to the IPC protocol, IL-2 (from 2.5 to 200 U/ml) or U50,488H (Wu et al, 1999) was infused for two cycles of 5 min followed by 5-min drug-free perfusion.
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To determine the involvement of OR subtypes, the mito-KATP channel, PKC, and ROS in the cardioprotection, antagonists, or inhibitors were administered for 10 min before the first ischemic preconditioning episode to 10 min after the second episode.
Drugs. Naltrindole (NTD), nor-binaltorphimine (nor-BNI), U50, 5-hydroxydecanoate (5-HD), 2,3,5-triphenyl-tetrazolium chloride, glybenclamide (Gly), chelerythrine (Che), GF 109203X (GF), N-acetylcysteine (NAC), N-(2-mercaptopropionyl)-glycine (2-MPG), and the LDH kit were purchased from Sigma-Aldrich. IL-2 was purchased from Shanghai Huaxin High Biotechnology Inc. (Shanghai, China).
NTD (Portoghese et al., 1988) and nor-BNI (Portoghese et al., 1994) are selective antagonists for - and -ORs, respectively, blocking them at a dose of 5 µM (Schoffelmeer et al., 1997; Wu et al., 1999; Wang et al., 2001a). 5-HD is a selective inhibitor of the mito-KATP channel, whereas glybenclamide is a nonselective blocker of KATP channels. The doses used were based on previous studies (Auchampach et al., 1992; Gross and Auchampach, 1992). GF and Che are PKC inhibitors, and the doses used were according to Liang (1997) and Ahmet et al. (2000). For inhibition of ROS, 2-MPG, a scavenger of free radicals, and NAC, a scavenger of hydroxyl radicals, were used at doses reported in previous studies (Klawitter et al., 2002; Yue et al., 2002).
Statistical Analysis. Statistical comparisons were performed by one-way analysis of variance, except for the dose-response data, which were analyzed by one-way analysis of variance and Dunnett's test. Differences of P < 0.05 are regarded as statistically significant.
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Results |
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LDH release was measured for the time course study. No LDH release was measurable in hearts subjected to 30 min of ischemia only. However, in hearts subjected to ischemia followed by 120 min of reperfusion, LDH was released with a peak at 5 min after the onset of reperfusion (Fig. 2B). Pretreatment with 50 U/ml IL-2 significantly reduced the release of LDH (Fig. 2B).
The effects of 50 U/ml IL-2 on infarct size (Fig. 3A) and LDH release (Fig. 3B) were compared with those preconditioned with two cycles of 5-min ischemia followed by 5 min of reperfusion. IL-2 pretreatment had effects similar to those induced by IPC.
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Effect of IL-2 on Infarct Size and LDH Release Induced by Myocardial Ischemia and Reperfusion upon OR Blockade. Because both - (Wu et al., 1999; Wang et al., 2001a) and (Tsuchida et al., 1998)-ORs have been shown to mediate the cardioprotection of preconditioning, we determined the effects of IL-2 upon blockade of either of these two receptors with selective antagonists. Blockade of -OR with 5 µM nor-BNI abolished the effects of 50 U/ml IL-2 on infarct size (Fig. 4A) and LDH release (Fig. 4B), whereas blockade of -OR with 5 µM NTD, known to block the effect of -OR activation (Portoghese et al., 1988), did not alter the effects of IL-2 on either infarct size (Fig. 4A) or LDH release (Fig. 4B). Neither of the OR antagonists alone had any effect on these parameters.
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Effect of IL-2 on Infarct Size and LDH Release Induced by Myocardial Ischemia and Reperfusion upon Blockade of the Mitochondrial KATP Channel or Protein Kinase C. Because blockade of the mito-KATP channel (Chen et al., 2003) or PKC (Wang et al., 2001b) has been shown to abolish/attenuate the cardioprotection of -OR stimulation with U50,488H, we determined whether blockade of these two effectors also abolished/attenuated the effects of pretreatment with IL-2. Blockade of the mito-KATP channel with either 5-HD, a selective inhibitor of the channel, or glybenclamide, a nonselective blocker of KATP channels, abolished the effects of IL-2 on infarct size (Fig. 5A) and LDH release (Fig. 5B). Similarly, blockade of PKC with its inhibitors Che or GF also abolished the effects of IL-2 on infarct size (Fig. 6A) and LDH release (Fig. 6B).
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The blockers of KATP channels (5-HD and glybenclamide), PKC inhibitors (Che and GF), and dimethyl sulfoxide, in which glybenclamide and GF were dissolved, had no effect when administered alone.
Effect of IL-2 on Infarct Size and LDH Release Induced by Myocardial Ischemia and Reperfusion upon Blockade of ROS. Because ROS have been implicated in cardioprotection of -OR stimulation (McPherson and Yao, 2001a,b), we determined whether the ROS were also involved in cardioprotection of pretreatment with IL-2 or U50,488H. Blockade of ROS with either 1 mM 2-MPG, a free radical scavenger, or 4 mM NAC, a hydroxyl radical scavenger, abolished the effects of both IL-2 and U50,488H on infarct size (Fig. 7A) and LDH release (Fig. 7B). Neither 2-MPG nor NAC alone had any effect.
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Effect of IL-2 on Postischemic Ventricular Function. If IL-2 exerts all its effects via the -OR, IL-2, and -OR stimulation should produce exactly the same effects on the heart We therefore determined the effect of IL-2 and U50,488H on hemodynamic parameters in the Langendorff isolated perfused heart. In all groups, ligation of left anterior descending artery resulted in a marked decrease in LVDP, LVDP x HR, ±dP/dtmax, and coronary flow (Table 1). The reductions in LVDP, LVDP x HR, ±dP/dtmax in the group treated with IL-2 (50 U/ml) were significantly attenuated during ischemia/reperfusion, suggesting that IL-2 improved the left ventricular parameters of contraction and relaxation of the heart suffered from challenge of ischemic injury. On the other hand, in the group treated with U50,488H, reductions of only LVDP, +dP/dtmax, and LVDP x HR during reperfusion were significantly attenuated. Neither of these two drugs altered the responses in LVEDP, HR, and CF during ischemia and reperfusion.
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Discussion |
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), IL-2 also confers cardioprotection. The most important finding of the present study is that the protective effect of IL-2 was mediated via -OR in the ischemia/reperfusion rat myocardium. This is based on the fact that the cardioprotective effect of pretreatment with IL-2 was blocked by blockade of -OR with a selective -OR antagonist, nor-BNI. In addition, the same signaling mechanisms, namely, the mito-KATP channel, PKC, and ROS, mediate the effects of both IL-2 and -OR stimulation. This is in agreement with the previous observation in our laboratory that the actions of IL-2 on contraction and Ca2+ homeostasis are blocked by blockade of the -OR in the heart (Cao et al., 2002). The interaction between IL-2 and OR has also been observed in other tissues. In phytohemagglutinin-stimulated human lymphocytes, naloxone, a nonselective OR antagonist, blunts the natural killer activity enhanced by IL-2 (Kay et al., 1990). It was also found that naloxone antagonizes the effects of IL-2 on behavioral sedation and the electrocorticogram in rats (De Sarro et al., 1990). In the rat, antiopioid peptide sera or naloxone attenuates the central analgesic effect of IL-2 (Jiang et al., 2000b; Song and Zhao, 2000). In the aortic ring, nor-BNI attenuates the endothelium-induced relaxation induced by IL-2 (Cao et al., 2003). It is important to note that we found in the present study that unlike nor-BNI, the -OR antagonist, naltrindole, the -OR antagonist, did not block/attenuate the effect of IL-2, suggesting that the -OR may not mediate the effect of IL-2. However, the possibility that 1- and 2-OR subtypes may have opposing effects, which would be antagonized by naltrindole, but not recognized with the protocol, cannot be excluded. Further studies using selective antagonists of -OR subtypes are warranted. The µ-OR was not investigated in the present study because it has been reported not to be involved in the regulation of cardiac function (Wong et al., 1990).
Besides IL-2, another interleukin and interferon-
have been shown to interact with the OR. Cyclic D-phe-cys-Try-D-Trp-Arg-Thr-Pen-Thr-NH2, a µ-OR antagonist, blocks the fever induced by IL-6 (Benamar et al., 2002). Pretreatment with naloxone inhibits the prolonged immobility time and analgesic effect induced by administration of interferon- (Jiang et al., 2000a; Makino et al., 2000). The results suggest that the OR may play many more important roles than previously thought. The OR may be a common entry point into the transmembrane signal transduction of extracellular nonopioid chemicals, including IL-2, interferon-, and other chemicals with a similar structure.
The possibility that ROS act as signaling molecules in myocardial tissues has recently gained considerable attention (Yao et al., 1999; Cohen et al., 2001). Yao et al. (1999) showed that ROS are generated by acetylcholine, which then protects chick cardiomyocytes against simulated ischemia in a mito-KATP-dependent manner. Cohen et al. (2001) found that activation of many Gi-coupled receptor systems mimic preconditioning through a ROS-dependent mechanism in the rabbit heart. 1-OR stimulation has been shown to induce an increased release of oxygen radicals from mitochondria in the heart, which was correlated with cardioprotection (McPherson and Yao, 2001a). We also observed in the present study that blockade of ROS with NAC and MPG abolished the cardioprotection of pretreatment with IL-2 or -OR stimulation. This observation provides further support of a mediatory role of ROS in cardioprotection of preconditioning. There is, however, evidence that NAC and some angiotensin-converting enzyme inhibitors modulate KATP channels (Han et al., 1996; Trapp et al., 1998; Wei et al., 1998), suggesting that these agents may confer cardioprotection by modulating the KATP channels.
In agreement with the previous observation that blockade of either the mito-KATP channel or PKC abolished/attenuated the cardioprotection of preconditioning (Uchiyama et al., 2003) or -OR stimulation with U50,488H (Wang et al., 2001a), we also observed that blockade of either of these two effectors abolished the cardioprotection of pretreatment with either IL-2. These are evidence in support of involvement of mito-KATP channels in cardioprotection. It has been shown that opening the mito-KATP channel leads to generation of free radicals (Krenz et al., 2002). It has also been shown that release of free radicals activates PKC (Simkhovich et al., 1998; Cohen et al., 2001) and mediates cardioprotection. It is likely that the cascade of events that occurs after activation of -OR by either IL-2 or U50,488H includes opening of the mito-KATP channel, release of free radicals from mitochondria, and activation of PKC, which may in turn activate other effectors. Further studies are warranted.
In the present study, we used 5-HD as a selective inhibitor of the mito-KATP channel. Blockade of cardioprotection with IL-2 by 5-HD was interpreted as indication of a mediatory role of the mito-KATP channel. There is, however, a recent report that suggested that 
-oxidation or metabolites of 5-HD may be responsible for abolition of cardioprotection of preconditioning (Hanley et al., 2003).
We found that both IL-2 and U50,488H exert beneficial effects on the heart during reperfusion. The effects are, however, not exactly the same. For example, IL-2 attenuated the reduction in -dP/dtmax, whereas U50488H did not. In addition, IL-2 improved the cardiac function during ischemia and reperfusion, whereas U50 only improved the cardiac function during reperfusion. The observation suggests that although IL-2 confers cardioprotection via -OR, it may also act on the heart independent of -OR.
In conclusion, the present study has provided the first evidence that pretreatment with IL-2 confers cardioprotection and the effect is -OR-mediated. Further study is needed to determine whether IL-2 activates the -OR directly or via increasing the release of -opioid peptides from the heart. The study has also provided the first evidence in support of involvement of ROS in cardioprotection of -OR stimulation with IL-2 or a selective -OR agonist.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: IPC, ischemia preconditioning; OR, opioid receptor; mito-KATP, mitochondrial ATP-sensitive potassium; PKC, protein kinase C; IL-2, interleukin-2; ROS, reactive oxygen species; LVEDP, left ventricular end diastolic pressure; HR, heart rate; LVDP, left ventricular developed pressure; CF, coronary flow; NTD, naltrindole; nor-BNI, nor-binaltorphimine; 5-HD, 5-hydroxydecanoate; Gly, glybenclamide; Che, chelerythrine; NAC, N-acetylcysteine; 2-MPG, N-(2-mercaptopropionyl)-glycine; U50,488H, (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide; GF 109203X, 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride.
Address correspondence to: Prof. Tak Ming Wong, Department of Physiology, 4/F, Laboratory Block, Faculty of Medicine Bldg., The University of Hong Kong, 21 Sassoon Rd., Hong Kong SAR, China. E-mail: wongtakm{at}hkucc.hku.hk
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