Abstract
It has been recently reported that release of erythropoietin could mediate the cardioprotective effects of remote renal preconditioning. However, the mechanism of erythropoietin-mediated cardioprotection in remote preconditioning is still unexplored. Therefore, the present study was designed to investigate the possible signal transduction pathway of erythropoietin-mediated cardioprotection in remote preconditioning in rats. Remote renal preconditioning was performed by four episodes of 5 min renal artery occlusion followed by 5 min reperfusion. Isolated rat hearts were perfused on Langendorff apparatus and were subjected to global ischemia for 30 min followed by 120 min reperfusion. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in coronary effluent to assess the degree of myocardial injury. Extent of myocardial infarct size and coronary flow rate was also measured. Remote renal preconditioning and erythropoietin preconditioning (5,000 IUkg−1, i.p.) attenuated ischemia-reperfusion-induced myocardial injury and produced cardioprotective effects. However, administration of diethyldithiocarbamic acid (150 mg kg−1 i.p.), a selective NFkB inhibitor, and glibenclamide (5 mg kg−1 i.p.), a selective KATP channel blocker, attenuated cardioprotective effects of remote preconditioning and erythropoietin preconditioning. However, administration of minoxidil (1 mg kg−1 i.v.), a selective KATP channel opener, restored the attenuated cardioprotective effects of remote preconditioning and erythropoietin preconditioning in diethyldithiocarbamic acid pretreated rats. These results suggest that KATP channel is a downstream mediator of NFkB activation in remote preconditioning and erythropoietin preconditioning. Therefore, it may be concluded that erythropoietin preconditioning and remote renal preconditioning trigger similar signaling mechanisms for cardioprotection, i.e., NFkB activation followed by opening of KATP channels.
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Abbreviations
- EPO:
-
Erythropoietin
- NFkB:
-
Nuclear factor kappa-B
- DDCA:
-
Diethyldithiocarbamic acid
- KH:
-
Kreb’s Henseleit
- LDH:
-
Lactate dehydrogenase
- CK:
-
Creatine kinase
- RRPC:
-
Remote renal preconditioning
- I/R:
-
ischemia-reperfusion
- PEG 400:
-
Polyethylene glycol
- 2,4-DNPH:
-
2,4-Dinitrophenylhydrazine
References
Przyklenk K, Baurer B, Ovize M et al (1993) Regional ischemic “preconditioning” protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 87:893–899
Singh M, Sharma A (2004) Mechanism of cardioprotective effect of remote aortic preconditioning. In: Dhalla NS, Angel RA, Pierce GN (eds) Pathophysiology of cardiovascular diseases. Kluwer Academic Publishers, Boston, pp 277–285
Tokuno S, Hinokiyama K, Tokuno K et al (2002) Spontaneous ischemic events in the brain and heart adapt the hearts of severely atherosclerotic mice to ischemia. Arterioscler Thromb Vasc Biol 22:995–1001. doi:10.1161/01.ATV.0000017703.87741.12
Patel HH, Moore J, Hsu AK et al (2002) Cardioprotection at a distance: mesenteric artery occlusion protects the myocardium via an opioid sensitive mechanism. J Mol Cell Cardiol 34:1317–1323. doi:10.1006/jmcc.2002.2072
Wang YP, Xu H, Mizoguchi K et al (2001) Intestinal ischemia induces late preconditioning against myocardial infarction: a role for inducible nitric oxide synthase. Cardiovasc Res 9:391–398. doi:10.1016/S0008-6363(00)00266-2
McClahan TB, Nao BS, Wolke LJ et al (1993) Brief renal occlusion and reperfusion reduces myocardial infarct size in rabbits. FASEB J 7:A118–A123
Skyschally A, Schulz R, Gres P et al (2003) Attenuation of ischemic preconditioning in pigs by scavenging of free radicals with ascorbic acid. Am J Physiol 284:H698–H703
Xia Z, Herijgers P, Nishida TS et al (2003) Remote preconditioning lessens the deterioration of pulmonary function after repeated coronary artery occlusion and reperfusion in sheep. Can J Anaesth 50:481–488
Schott RJ, Rohmann S, Braun ER et al (1990) Ischemic preconditioning reduces infarct size in swine myocardium. Circ Res 66:1133–1142
Liauw SK, Rubin BB, Lindsay TF et al (1996) Sequential ischemia/reperfusion results in contralateral skeletal muscle salvage. Am J Physiol 270:H1407–H1413
Loukogeorgakis SP, Donald A, Charakida M et al (2005) Remote ischemic preconditioning provides early and late protection against endothelial ischemia reperfusion injury in humans. J Am Coll Cardiol 46:450–456. doi:10.1016/j.jacc.2005.04.044
Diwan V, Jaggi AS, Singh M, Singh N, Singh D (2008) Possible involvement of erythropoietin in remote renal preconditioning induced cardioprotection in rats. J Cardiovasc Pharmacol 51:126–130
Daghman NA, Elder GE, Savage GA et al (1999) Erythropoietin production: evidence for multiple oxygen sensing pathways. Ann Hematol 78:275–278. doi:10.1007/s002770050514
Kaelin WG Jr (2002) How oxygen makes its presence felt. Genes Dev 16:1441–1445. doi:10.1101/gad.1003602
Bohlius J, Weingart O, Trelle S et al (2006) Cancer-related anemia and recombinant human erythropoietin—an updated overview. Nat Clin Pract Oncol 3:152–164. doi:10.1038/ncponc0451
Sola A, Rogido M, Lee BH et al (2005) Erythropoietin after focal cerebral ischemia activates the janus kinase–signal transducer and activator of transcription signaling pathway and improves brain injury in postnatal day 7 rats. Pediatr Res 57:481–487. doi:10.1203/01.PDR.0000155760.88664.06
Locatelli F, Alijama P, Barany P et al (2004) European best practice guidelines group. Revised European best practice guidelines for the management of anemia in patients with chronic renal failure. Nephrol Dial Transplant 19:1–47. doi:10.1093/ndt/gfg390
Bianchi R, Buyukakilli B, Brines M et al (2004) Erythropoietin both protects from and reverses experimental diabetic neuropathy. Proc Natl Acad Sci USA 101:823–828. doi:10.1073/pnas.0307823100
Sharples EJ, Patel N, Brown P et al (2004) Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. J Am Soc Nephrol 15:2115–2124. doi:10.1097/01.ASN.0000135059.67385.5D
Bittorf T, Buchse T, Sasse T, Jaster R, Brock J (2001) Activation of the transcription factor NF-kappaB by the erythropoietin receptor: structural requirements and biological significance. Cell Signal 13:673–681. doi:10.1016/S0898-6568(01)00189-9
Liu X, Shen J, Jin Yi, Duan M, Xu J (2006) Recombinant human erythropoietin (rhEPO) preconditioning on nuclear factor-kappa B (NF-kB) activation & proinflammatory cytokines induced by myocardial ischaemia-reperfusion. Indian J Med Res 124:343–354
Shi Y, Rafiee P, Su J, Pritchard KA Jr, Tweddell JS, Baker JE (2004) Acute cardioprotective effects of erythropoietin in infant rabbits are mediated by activation of protein kinases and potassium channels. Basic Res Cardiol 99:173–182. doi:10.1007/s00395-004-0455-x
Valen G, Yan ZQ, Hansson GK (2001) Nuclear factor kappa-B and the heart. J Am Coll Cardiol 38:307–314. doi:10.1016/S0735-1097(01)01377-8
Kis A, Yellon DM, Baxter GF (2003) Role of nuclear factor-kappa B activation in acute ischemia-reperfusion injury in myocardium. Br J Pharmacol 138:894–900. doi:10.1038/sj.bjp. 0705108
Xuan YT, Tang XL, Banerjee S et al (1999) Nuclear factor KB plays an essential role in the late phase of ischemic preconditioning in conscious rabbits. Circ Res 84:1095–1099
Kant R, Diwan V, Jaggi AS, Singh N, Singh D (2008) Remote renal preconditioning-induced cardioprotection: a key role of hypoxia inducible factor-prolyl 4-hydroxylases. Mol Cell Biochem 312:25–31. doi:10.1007/s11010-008-9717-5
Noma A (1983) ATP-regulated K+ channels in cardiac muscle. Nature 305:147–148. doi:10.1038/305147a0
Kevelaitis E, Oubenaissa A, Peynet J, Mouas C, Menasche P (1999) Preconditioningby mitochondrial ATP-sensitive potassium channel openers: an effective approach for improving the preservation of heart transplants. Circulation 100:345–350
Cao CM, Gao QXQ, Chen M, Wong TM (2005) Calcium-activated potassium channel triggers cardioprotection of ischemic preconditioning. J Pharmacol Exp Ther 312:644–650. doi:10.1124/jpet.104.074476
Kristiansen SB, Henning O, Kharbanda RK, Nielsen-Kudsk JE, Schmidt MR, Redington AN et al (2005) Remote preconditioning reduces ischemic injury in the explanted heart by a KATP channel-dependent mechanism. Am J Physiol Heart Circ Physiol 288:H1252–H1256. doi:10.1152/ajpheart.00207.2004
Mabanta L, Valane P, Borne J, Frame MD (2006) Initiation of remote microvascularpreconditioning requires KATP channel activity. Am J Physiol Heart Circ Physiol 290:H264–H271. doi:10.1152/ajpheart.00455.2005
Pell TJ, Baxter GF, Yellon DM, Drew GM (1998) Renal ischaemia preconditions myocardium: role of adenosine receptors and ATP-sensitive potassium channels. Am J Physiol 275:H1542–H1547
Langendorff O (1895) Untersuchungen amuber lebenderer saugethierherzen. Pfluger Arch Gesmate Physiolgie 61:291–332. doi:10.1007/BF01812150
Chopra K, Singh M, Kaul N et al (1992) Decrease of myocardial infarct size with desferrioxamine: possible role of oxygen free radicals in its ameliorative effect. Mol Cell Biochem 113:71–76. doi:10.1007/BF00230887
King JA (1959) A routine method for estimation of lactate dehydrogenase activity. J Med Lab Technol 16:265–272
Swanson JR, Wilkinson JH (1972) Measurements of creatine kinase in serum. Stand Methods Clin Chem 7:33
Mukundan H, Resta TC, Kanagy NL (2002) 17-Estradiol decreases hypoxic induction of erythropoietin gene expression. Am J Physiol 283:R496–R504
Müllenheim J, Molojavyi A, Preckel B et al (2001) Thiopentone does not block ischemic preconditioning in the isolated rat heart. Can J Anaesth 48:784–789
Egrie JC (1986) Characterization and biological effects of recombinant human erythropoietin. Immunobiology 172:213–224
Sharma A, Singh M (2001) Protein kinase C activation and cardioprotective effect of preconditioning with oxidative stress in isolated rat heart. Mol Cell Biochem 219:1–6. doi:10.1023/A:1011038531656
Jaggi AS, Singh M, Sharma A, Singh S, Singh N (2007) Cardioprotective effects of mast cell modulators in ischemia-reperfusion-induced injury in rats. Methods Find Exp Clin Pharmacol 29:593–600
Rehni AK, Shri R, Singh M (2007) Remote ischaemic preconditioning and prevention of cerebral injury. Indian J Exp Biol 45:247–252
Acknowledgment
The authors are grateful to Dr. Ashok Kumar Tiwary, Head, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India for supporting this study and providing technical facilities for the work.
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Diwan, V., Kant, R., Jaggi, A.S. et al. Signal mechanism activated by erythropoietin preconditioning and remote renal preconditioning-induced cardioprotection. Mol Cell Biochem 315, 195–201 (2008). https://doi.org/10.1007/s11010-008-9808-3
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DOI: https://doi.org/10.1007/s11010-008-9808-3