PROBABLE ROLE OF PPAR-ALPHA IN ATTENUATED CARDIOPROTECTIVE EFFECT OF ISCHEMIC PRECONDITIONING IN HYPERLIPIDEMIC RAT HEARTS

Authors

  • Gurfateh Singh "Institute of Pharmacy, NIMS University, Jaipur, Rajasthan"
  • Khan Mu
  • Razia Khana

Abstract

 

 Objectives: The present study has been designed in order to investigate the probable role of peroxisome proliferator activated receptor-alpha (PPAR-α) in hyperlipidemia-induced attenuation of cardioprotective effect of ischemic preconditioning (IPC).

Methods: Experimental hyperlipidemia was produced by feeding high fat diet to rats for a period of 28 days. Isolated langendorff's perfused normal and hyperlipidemic rat hearts were subjected to global ischemia for 30 min followed by reperfusion for 120 min. The myocardial infarct size was assessed macroscopically using triphenyltetrazolium chloride (TTC) staining. Coronary effluent was analyzed for lactate dehydrogenase (LDH) and creatine kinase (CK) release to assess the extent of cardiac injury. Moreover, the oxidative stress in heart was assessed by measuring thiobarbituric acid reactive substance (TBARS), superoxide anion generation and reduced form of glutathione (GSH).

Results: The ischemia-reperfusion (I/R) has been noted to induce oxidative stress by increasing TBARS, superoxide anion generation and decreasing reduced form of glutathione in normal and hyperlipidemic rat hearts. Moreover, I/R produced myocardial injury, which was assessed in terms of increase in myocardial infarct size, LDH and CK release in coronary effluent and decrease in coronary flow rate in normal and hyperlipidemic rat hearts. In addition, the hyperlipidemic rat hearts showed enhanced I/R-induced myocardial injury with high degree of oxidative stress as compared with normal rat hearts subjected to I/R. Four episodes of IPC (5 min each) afforded cardioprotection against I/R-induced myocardial injury in normal rat hearts as assessed in terms of improvement in coronary flow rate and reduction in myocardial infarct size, LDH, CK and oxidative stress. On the other hand, IPC mediated myocardial protection against I/R-injury was abolished in hyperlipidemic rat hearts. Treatment with Fenofibrate (100 mg/kg/day, i.p.), an activator of PPAR-α has not affected the cardioprotective effect of IPC in normal rat hearts, but its treatment markedly restored the cardioprotective potential of IPC in hyperlipidemic rat hearts.

Conclusion: It is suggested that the high degree of oxidative stress produced in hyperlipidemic rat heart during reperfusion and consequent down-regulation of PPAR-α may be responsible to abolish the cardioprotective potential of IPC against I/R induced myocardial injury.

Keywords: Hyperlipidemia, Ischemia-reperfusion injury, Ischemic preconditioning, Fenofibrate, Proliferator activated receptor-alpha.

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Author Biography

Gurfateh Singh, "Institute of Pharmacy, NIMS University, Jaipur, Rajasthan"

Research Schloar, Department of Pharmacology, Institute of Pharmacy, NIMS University, Shobha Nagar, Jaipur-303121, Rajasthan, India

References

Gorudko IV, Kostevich VA, Sokolov AV, Shamova EV, Buko IV, Konstantinova EE, et al. Functional activity of neutrophils in diabetes mellitus and coronary heart disease: Role of myeloperoxidase in the development of oxidative stress. Bull Exp Biol Med 2012;154(1):23-6.

Linkermann A, Bräsen JH, Darding M, Jin MK, Sanz AB, Heller JO, et al. Two independent pathways of regulated necrosis mediate ischemia-reperfusion injury. Proc Natl Acad Sci U S A 2013;110(29):12024-9.

Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 1986;74(5):1124-36.

Rohilla A, Khan MU, Khanam R. Cardioprotective role of atorvastatin in hyperhomocysteinemic rat hearts. Asian J Pharm Clin Res 2012;5(2):120-3.

Hausenloy DJ, Yellon DM. Preconditioning and post conditioning: United at reperfusion. Pharmacol Ther 2007;116:173-91.

Andersen A, Povlsen JA, Bøtker HE, Nielsen-Kudsk JE. Ischemic preconditioning reduces right ventricular infarct size through opening of mitochondrial potassium channels. Cardiology 2012;123(3):177-80.

Hausenloy DJ. Cardioprotection techniques: Preconditioning, post conditioning and remote con-ditioning (basic science). Curr Pharm Des 2013;19:4544-63.

Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res 2003;60(3):617-25.

Angeloni C, Motori E, Fabbri D, Malaguti M, Leoncini E, Lorenzini A, et al. H2O2 preconditioning modulates phase II enzymes through p38 MAPK and PI3K/Akt activation. Am J Physiol Heart Circ Physiol 2011;300(6):H2196-205.

Giricz Z, Lalu MM, Csonka C, Bencsik P, Schulz R, Ferdinandy P. Hyperlipidemia attenuates the infarct size-limiting effect of ischemic preconditioning: Role of matrix metalloproteinase-2 inhibition. J Pharmacol Exp Ther 2006;316(1):154-61.

Sasaki H, Ogawa K, Shimizu M, Mori C, Takatsuka H, Okazaki F, et al. The insulin sensitizer pioglitazone improves the deterioration of ischemic preconditioning in type 2 diabetes mellitus rats. Int Heart J 2007;48(5):623-35.

Avraamidou A, Marinis A, Asonitis S, Perrea D, Polymeneas G, Voros D, et al. The impact of ischemic preconditioning on hemodynamic, biochemical and inflammatory alterations induced by intra-abdominal hypertension: An experimental study in a porcine model. Langenbecks Arch Surg 2012;397(8):1333-41.

Balakumar P, Babbar L. Preconditioning the hyperlipidemic myocardium: Fact or fantasy? Cell Signal 2012;24(3):589-95.

Kamesh V, Sumathi T. Effect of Bacopa monniera linn. in attenuating hepatic oxidative stress in hypercholesterolemic induced rats. Asian J Pharm Clin Res 2012;5(3):90-5.

Tonini CL, Campagnaro BP, Louro LP, Pereira TM, Vasquez EC, Meyrelles SS. Effects of aging and hypercholesterolemia on oxidative stress and DNA Damage in bone marrow mononuclear cells in apolipoprotein E-deficient mice. Int J Mol Sci 2013;14(2):3325-42.

Jahnavi N, Naidu PP, Rao K, Karunasree CP. Antihyperlipidemic effect of Asparagus gonoclados baker against cholesterol diet induced hyperlipidemia in rats. Asian J Pharm Clin Res 2014;7(2):212-5.

Samant P, Badade ZG, Rai S. Effect of hyperuricemia on serum nitric oxide levels in diabetic patients with hyperlipidemia. Int J Biol Med Res 2012;3:1338-41.

Lalloyer F, Wouters K, Baron M, Caron S, Vallez E, Vanhoutte J, et al. Peroxisome proliferator-activated receptor-alpha gene level differently affects lipid metabolism and inflammation in apolipoprotein E2 knock-in mice. Arterioscler Thromb Vasc Biol 2011;31(7):1573-9.

Guellich A, Damy T, Lecarpentier Y, Conti M, Claes V, Samuel JL, et al. Role of oxidative stress in cardiac dysfunction of PPARalpha-/- mice. Am J Physiol Heart Circ Physiol 2007;293(1):H93-102.

Loichot C, Jesel L, Tesse A, Tabernero A, Schoonjans K, Roul G, et al. Deletion of peroxisome proliferator-activated receptor-alpha induces an alteration of cardiac functions. Am J Physiol Heart Circ Physiol 2006;291(1):H161-6.

Bulhak AA, Jung C, Ostenson CG, Lundberg JO, Sjöquist PO, Pernow J. PPAR-alpha activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: Involvement of the PI3-Kinase/Akt and NO pathway. Am J Physiol Heart Circ Physiol 2009;296(3):H719-27.

Ravingerová T, Carnická S, Nemceková M, Ledvényiová V, Adameová A, Kelly T, et al. PPAR-alpha activation as a preconditioning-like intervention in rats in vivo confers myocardial protection against acute ischaemia-reperfusion injury: Involvement of PI3K-Akt. Can J Physiol Pharmacol 2012;90(8):1135-44.

Balakumar P, Rohilla A, Mahadevan N. Pleiotropic actions of fenofibrate on the heart. Pharmacol Res 2011;63(1):8-12.

Zulet MA, Barber A, Garcin H, Higueret P, Martínez JA. Alterations in carbohydrate and lipid metabolism induced by a diet rich in coconut oil and cholesterol in a rat model. J Am Coll Nutr 1999;18(1):36-42.

Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18(6):499-502.

Langendorff O. Untersuchungen am uberlebenden Saugethierherzen. Bonn. Arch Ges Physiol Mensch Thiere 1895;61:291-332.

Parikh V, Singh M. Possible role of adrenergic component and cardiac mast cell degranulation in preconditioning-induced cardioprotection. Pharmacol Res 1999;40(2):129-37.

Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979;95(2):351 8.

Wang HD, Pagano PJ, Du Y, Cayatte AJ, Quinn MT, Brecher P, et al. Superoxide anion from the adventitia of the rat thoracic aorta inactivates nitric oxide. Circ Res 1998;82:810-8.

Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med 1963;61:882-8.

31. Amani M, Jeddi S, Ahmadiasl N, Usefzade N, Zaman J. Effect of HEMADO on level of CK-MB and LDH enzymes after ischemia/reperfusion injury in isolated rat heart. Bioimpacts 2013;3(2):101-4.

Yadav HN, Singh M, Sharma PL. Pharmacological inhibition of GSK-3ß produces late phase of cardioprotection in hyperlipidemic rat: Possible involvement of HSP 72. Mol Cell Biochem 2012;369(1 2):227-33.

Ungvari Z, Csiszar A, Edwards JG, Kaminski PM, Wolin MS, Kaley G, et al. Increased superoxide production in coronary arteries in hyperhomocysteinemia: Role of tumor necrosis factor-alpha, NAD(P) H oxidase, and inducible nitric oxide synthase. Arterioscler Thromb Vasc Biol 2003;23:418-24.

Tabassum H, Parvez S, Pasha ST, Banerjee BD, Raisuddin S. Protective effect of lipoic acid against methotrexate-induced oxidative stress in liver mitochondria. Food Chem Toxicol 2010;48(7):1973-9.

Yadav HN, Singh M, Sharma PL. Modulation of the cardioprotective effect of ischemic preconditioning in hyperlipidaemic rat heart. Eur J Pharmacol 2010;643(1):78-83.

Yellon DM, Downey JM. Preconditioning the myocardium: From cellular physiology to clinical cardiology. Physiol Rev 2003;83(4):1113 51.

Vinten-Johansen J, Zhao ZQ, Jiang R, Zatta AJ, Dobson GP. Preconditioning and postconditioning: Innate cardioprotection from ischemia-reperfusion injury. J Appl Physiol (1985)2007;103(4):1441-8.

Kim T, Yang Q. Peroxisome-proliferator-activated receptors regulate redox signaling in the cardiovascular system. World J Cardiol 2013;5(6):164-74.

Varga ZV, Kupai K, Szucs G, Gáspár R, Pálóczi J, Faragó N, et al. MicroRNA-25-dependent up-regulation of NADPH oxidase 4 (NOX4) mediates hypercholesterolemia-induced oxidative/nitrative stress and subsequent dysfunction in the heart. J Mol Cell Cardiol 2013;62:111 21.

Becker J, Delayre-Orthez C, Frossard N, Pons F. The peroxisome proliferator-activated receptor a agonist fenofibrate decreases airway reactivity to methacholine and increases endothelial nitric oxide synthase phosphorylation in mouse lung. Fundam Clin Pharmacol 2012;26(3):340-6.

Yeh CH, Chen TP, Lee CH, Wu YC, Lin YM, Lin PJ. Cardiomyocytic apoptosis following global cardiac ischemia and reperfusion can be attenuated by peroxisome proliferator-activated receptor alpha but not gamma activators. Shock 2006;26(3):262-70.

Wu KK. Peroxisome proliferator-activated receptors protect against apoptosis via 14-3-3. PPAR Res 2010;2010:Article ID 417646, doi:10.1155/2010/417646..

Published

01-11-2014

How to Cite

Singh, G., K. Mu, and R. Khana. “PROBABLE ROLE OF PPAR-ALPHA IN ATTENUATED CARDIOPROTECTIVE EFFECT OF ISCHEMIC PRECONDITIONING IN HYPERLIPIDEMIC RAT HEARTS”. Asian Journal of Pharmaceutical and Clinical Research, vol. 7, no. 5, Nov. 2014, pp. 67-74, https://mail.innovareacademics.in/journals/index.php/ajpcr/article/view/2337.

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