Abstract
Brief intermittent episodes of ischemia and reperfusion could reduce infarct size, a phenomenon called “postconditioning” at the onset of reperfusion after a prolonged period of ischemia. To investigate whether the opioid receptors and signaling factor JAK-STAT might be responsible for the cardioprotection in ischemic postconditioning, and the possible molecular machinery of cardioprotection. Hundred and twenty healthy New Zealand rabbits were divided into six groups. The myocardial infarct size, cardiac myocyte apoptosis, BCL-2 and P-Stat3 protein expression were tested in the current study. The results suggested that ischemic postconditioning might increase BCL-2 protein expression by activating the opioid receptors and JAK-STAT signaling pathway, and also to reduce ischemia-reperfusion-induced cardiomyocyte apoptosis and to play a key role in myocardial protection. However, further research still needs to be done to unravel the underlying mechanisms.
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References
Piper HM, Garcia-Dorado D, Ovize MA (1998) Fresh look at reperfusion injury. Cardiovasc Res 38:291–300
Vinten-Johansen J (2004) Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc Res 61:481–497
Cohen MV, Downey JM (2001) Ischemic preconditioning: description, mechanism, and significance. In: Sperelakis N, Kurachi Y, Terzic A, Cohen MV (eds) Heart physiology and pathophysiology, 4th edn. Academic Press, San Diego, pp 867–885
Kin H, Zatta AJ, Lofye MT, Amerson BS, Halkos ME, Kerendi F, Zhao ZQ, Guyton RA, Headrick JP, Vinten-Johansen J (2005) Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine. Cardiovasc Res 67:124–133
Heusch G, Boengler K, Schulz R (2008) Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation 118:1915–1919
Skyschally A, Van Caster P, Boengler K, Gres P, Musiolik J, Schilawa D, Schulz R, Heusch G (2009) Ischemic postconditioning in pigs: no causal role for RISK activation. Circ Res 104:15–18
Yang XM, Proctor JB, Cui L, Krieg T, Downey JM, Cohen MV (2004) Multiple brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. Am Coll Cardiol 44:1103–1110
Farb A, Kolodgie FD, Jenkins M, Virmani R (1993) Myocardial infarct extension during reperfusion after coronary artery occlusion: pathologic evidence. J Am Coll Cardiol 21:1245–1253
Van den Hoek TL, Shao Z, Li C, Zak R, Schumacker PT, Becker LB (1996) Reperfusion injury in cardiac myocytes after simulated ischemia. Am J Physiol 270:H1334–H1341
Matsumura K, Jeremy RW, Schaper J, Becker LC (1998) Progression of myocardial necrosis during reperfusion of ischemic myocardium. Circulation 97:795–804
Karaali ZE, Sozen S, Yurdum M, Cacina C, Toptas B, Gok O, Agachan B (2010) Effect of genetic variants of chemokine receptors on the development of myocardial infarction in Turkish population. Mol Biol Rep. Feb 25. [Epub ahead of print]
Yang J, Zhang XD, Yang J, Ding JW, Liu ZQ, Li SG, Yang R (2010) The cardioprotective effect of fluvastatin on ischemic injury via down-regulation of toll-like receptor 4. Mol Biol Rep. Feb 4. [Epub ahead of print]
Chen LL, Zhu TB, Yin H, Huang J, Wang LS, Cao KJ, Yang ZJ (2009) Inhibition of MAPK signaling by eNOS gene transfer improves ventricular remodeling after myocardial infarction through reduction of inflammation. Mol Biol Rep. Nov 12. [Epub ahead of print]
Luan B, Han Y, Zhang X, Kang J, Yan C (2010) Association of the SDF1-3′A polymorphism with susceptibility to myocardial infarction in Chinese Han population. Mol Biol Rep 37(1):399–403
Yao YT, Li LH, Chen L, Wang WP, Li LB, Gao CQ (2009) Sevoflurane postconditioning protects isolated rat hearts against ischemia-reperfusion injury: the role of radical oxygen species, extracellular signal-related kinases 1/2 and mitochondrial permeability transition pore. Mol Biol Rep. Aug 20. [Epub ahead of print]
Yilmaz E, Akar R, Eker ST, Deda G, Adiguzel Y, Akar N (2010) Relationship between functional promoter polymorphism in the XBP1 gene (-116C/G) and atherosclerosis, ischemic stroke and hyperhomocysteinemia. Mol Biol Rep 37(1):269–272
Tang J, Wang J, Song H, Huang Y, Yang J, Kong X, Guo L, Zheng F, Zhang L (2010) Adenovirus-mediated stromal cell-derived factor-1 alpha gene transfer improves cardiac structure and function after experimental myocardial infarction through angiogenic and antifibrotic actions. Mol Biol Rep 37(4):1957–1969
Hou X, Wu X, Ma J, Lv X, Jin X (2010) Erythropoietin augments the efficacy of therapeutic angiogenesis induced by allogenic bone marrow stromal cells in a rat model of limb ischemia. Mol Biol Rep 37(3):1467–1475
Ganesan B, Buddhan S, Anandan R, Sivakumar R, AnbinEzhilan R (2010) Antioxidant defense of betaine against isoprenaline-induced myocardial infarction in rats. Mol Biol Rep 37(3):1319–1327
Chen Z, Zhang X, Ma G, Qian Q, Yao Y (2010) Association study of four variants in KCNQ1 with type 2 diabetes mellitus and premature coronary artery disease in a Chinese population. Mol Biol Rep 37(1):207–212
Chen Z, Ma G, Qian Q, Yao Y, Feng Y, Tang C (2009) Toll-like receptor 8 polymorphism and coronary artery disease. Mol Biol Rep 36(7):1897–1901
Chen Z, Qian Q, Ma G, Wang J, Zhang X, Feng Y, Shen C, Yao Y (2009) A common variant on chromosome 9p21 affects the risk of early-onset coronary artery disease. Mol Biol Rep 36(5):889–893
Liu B, Li W, Li Y, Wang Z, Li H, Liu P, Fu J (2009) Protective effects of N-acetylcysteine in isoproterenol-induced myocardium injury in rats. Mol Biol Rep 36(4):761–765
Ni Y, Zhang J (2009) Association of deoxyribonuclease I genetic polymorphisms with myocardial infarction in Han Chinese. Mol Biol Rep 36(3):595–601
Wan J, Xiong C, Zheng F, Zhou X, Huang C, Jiang H (2008) Study of Kir6.2/KCNJ11 gene in a sudden cardiac death pedigree. Mol Biol Rep 35(2):119–123
Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA et al (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol 285:H579–H588
Zatta AJ, Kin H, Lee G, Wang N, Jiang R, Lust R, Reeves JG, Mykytenko J, Guyton RA, Zhao ZQ, Vinten-Johansen J (2006) Infarct-sparing effect of myocardial postconditioning is dependent on protein kinase C signaling. Cardiovasc Res 70:315–324
Kin H, Zhao ZQ, Sun HY, Wang NP, Corvera JS, Halkos ME, Kerendi F, Guyton RA, Vinten-Johansen J (2004) Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res 62:74–85
Halkos ME, Kerendi F, Corvera JS, Wang NP, Kin H, Payne CS, Sun HY, Guyton RA, Vinten-Johansen J, Zhao ZQ (2004) Myocardial protection with postconditioning is not enhanced by ischemic preconditioning. Ann Thorac Surg 78:961–969
Sun HY, Wang NP, Kerendi F, Halkos M, Kin H, Guyton RA, Vinten-Johansen J, Zhao ZQ (2005) Hypoxic postconditioning reduces cardiomyocyte loss by inhibiting the generation of reactive oxygen species and intracellular calcium overload. Am J Physiol Heart Circ Physiol 288:H1900–H1908
Tsang A, Hausenloy DJ, Mocanu MM, Yellon DM (2004) Postconditioning: a form of “modified reperfusion” protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway. Circ Res 95:230–232
Yang XM, Krieg T, Cui L, Downey JM, Cohen MV (2004) NECA and bradykinin at reperfusion reduce infarction in rabbit hearts by signaling through PI3 K, ERK, and NO. J Mol Cell Cardiol 36:411–421
Bell RM, Yellon DM (2003) Bradykinin limits infarction when administered as an adjunct to reperfusion in mouse heart: the role of PI3 K, Akt and eNOS. J Mol Cell Cardiol 35:185–193
Liao Z, Brar BK, Cai Q, Stephanou A, O′Leary RM, Pennica D, Yellon DM, Latchman DS (2002) Cardiotrophin-1 (CT-1) can protect the adult heart from injury when added both prior to ischemia and at reperfusion. Cardiovasc Res 53:902–910
Jonassen AK, Sack MN, Mjøs OD, Yellon DM (2001) Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling. Circ Res 89:1191–1198
Baxter GF, Mocanu MM, Brar BK, Latchman DS, Yellon DM (2001) Cardioprotective effects of transforming growth factor-beta 1 during early reoxygenation or reperfusion are mediated by p42/p44 MAPK. J Cardiovasc Pharmacol 38:930–939
Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M (2005) Postconditioning inhibits mitochondrial permeability transition. Circulation 111:194–197
Argaud L, Prigent AF, Chalabreysse L, Loufouat J, Lagarde M, Ovize M (2004) Ceramide in the antiapoptotic effect of ischemic preconditioning. Am J Physiol 286:H246–H251
Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136
Philipp S, Yang XM, Cui L, Davis AM, Downey JM, Cohen MV (2006) Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade. Cardiovasc Res 70:308–314
Braunwald E, Kloner RA (1985) Myocardial reperfusion: a double-edged sword? J Clin Invest 76:1713–1719
Zhao ZQ, Sun HY, Wang NP, Kerendi F, Guyton RA, Vinten-Johansen J (2003) Hypoxic post-conditioning reduces cardiomyocyte loss by inhibiting reactive oxygen species-triggered mitochondrial calcium overload. Circulation 108(suppl IV):174
Skyschally A, van Caster P, Iliodromitis EK, Schulz R, Kremastinos DT, Heusch G (2009) Ischemic postconditioning: experimental models and protocol algorithms. Basic Res Cardiol 104:469–483
Bolli R, Dawn B, Xuan YT (2003) Role of the JAK-STAT pathway in protection against myocardial ischemia/reperfusion injury. Trends Cardiovasc 13:72–79
Gross ER, Hsu AK, Gross GJ (2006) The JAK-STAT pathway is essential for opioid-induced cardioprotection: JAK2 as a mediator of STAT3, Akt, and GSK-3 beta. Am J Physiol Heart Circ Physiol 291:H827–H834
Booz GW, Day JN, Baker KM (2002) Interplay between the cardiac renin angiotensin system and JAK-STAT signaling: role in cardiac hypertrophy, ischemia/reperfusion dysfunction, and heart failure. J Mol Cell Cardiol 34:1443–1453
Negoro S, Kunisada K, Tone E, Funamoto M, Oh H, Kishimoto T, Yamauchi-Takihara K (2000) Activation of JAK-STAT pathway transduces cytoprotective signal in rat acute myocardial infarction. Cardiovasc Res 47:797–805
Schwarze MM, Hawley RG (1995) Prevention of myeloma cell apoptosis by ectopic BCL-2 expression or interleukin 6-mediated up-regulation of BCL-xL. Cancer Res 55:2262–2265
Kunisada K, Negoro S, Tone E, Funamoto M, Osugi T, Yamada S, Okabe M, Kishimoto T, Yamauchi-Takihara K (2000) Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy. Proc Natl Acad Sci USA 4:315–319
Hattori R, Maulik N, Otani H, Zhu L, Cordis G, Engelman RM, Siddiqui MA, Das DK (2001) Role of STAT3 in ischemic preconditioning. J Mol Cell Cardiol 33:1929–1936
Boengler K, Buechert A, Heinen Y, Roeskes C, Hilfiker-Kleiner D, Heusch G, Schulz R (2008) Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice. Circ Res 102:131–135
Boengler K, Hilfiker-Kleiner D, Drexler H, Heusch G, Schulz R (2008) The myocardial JAK-STAT pathway: from protection to failure. Pharmacol Ther 120:172–185
Jang Y, Xi J, Wang H, Mueller RA, Norfleet EA, Xu Z (2008) Postconditioning prevents reperfusion injury by activating delta-opioid receptors. Anesthesiology 108:243–250
Zatta AJ, Kin H, Yoshishige D, Jiang R, Wang N, Reeves JG, Mykytenko J, Guyton RA, Zhao ZQ, Caffrey JL, Vinten-Johansen J (2008) Evidence that cardioprotection by postconditioning involves preservation of myocardial opioid content and selective opioid receptor activation. Am J Physiol Heart Circ Physiol 294:H1444–H1451
Mayfield KP, D′Alecy LG (1994) Delta-1 opioid agonist acutely increases hypoxic tolerance. J Pharmacol Exp Ther 268:74–77
Chien S, Oeltgen PR, Diana JN, Salley RK (1994) Extension of tissue survival time in multiorgan block preparation with a delta opioid DADLE [(D-Ala2, D-Leu5)-enkephalin). J Thorac Cardiovasc Surg 107:964–967
Schultz JE, Hsu AK, Gross GJ (1996) Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart. Circ Res 78:1100–1104
Peart JN, Gross ER, Reichelt ME, Hsu A, Headrick JP, Gross GJ (2008) Activation of kappa-opioid receptors at reperfusion affords cardioprotection in both rat and mouse hearts. Basic Res Cardiol 103:454–463
Schultz JJ, Rose E, Yao Z, Gross GJ (1995) Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts. Am J Physiol 268:H2157–H2161
Chien GL, Tang Y, Van Winkle DM (1995) Stereospecific blockade of myocardial ischemic preconditioning by naloxone. Circulation 92(suppl 8):381–389
Haunstetter A, Izumo S (1998) Apoptosis basic mechanisms and implications for cardio via secular Disease. Circ Res 82:1111–1129
Vinten-Johansen J, Zhao ZQ, Zatta AJ, Kin H, Halkos ME, Kerendi F (2005) Postconditioning–A new link in nature′s armor against myocardial ischemia-reperfusion injury. Basic Res Cardiol 100:295–310
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L. You, L. Li are Co-first Author.
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You, L., Li, L., Xu, Q. et al. Postconditioning reduces infarct size and cardiac myocyte apoptosis via the opioid receptor and JAK-STAT signaling pathway. Mol Biol Rep 38, 437–443 (2011). https://doi.org/10.1007/s11033-010-0126-y
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DOI: https://doi.org/10.1007/s11033-010-0126-y