Health  Vol.2 No.8 , August 2010
Apelin-12 improves metabolic and functional recovery of rat heart after global ischemia
Abstract: This work was designed to explore efficacy of apelin-12 (A-12) as a cardioprotective agent when given before ischemia or at reperfusion using the isolated working heart model. Hearts of male Wistar rats were subjected to 30-min stabilization period followed by 35-min global ischemia and 30-min reperfusion. A short-term infusion of Krebs-Henseleit buffer (KHB) con-taining A-12 (35, 70, 140, 280 or 560 ?M) was ap-plied prior to ischemia (A-12-I) or at onset of reperfusion (A-12-R). KHB infusion was used as control. A-12 infusions induced a dose-dependent increase in recovery of coronary flow, contractile and pump function during reperfu-sion, with the largest augmentation of these indices in the A-12-I group. Both A-12 groups exhibited a significant reduction of LV diastolic pressure rise during reperfusion compared with control. Enhanced functional recovery in the A-12-I group was combined with a decrease in LDH leakage in perfusate on early reperfusion (by 36% vs. control, p < 0.05). Preischemic infusion of 140 ?M A-12 markedly increased myocardial ATP content, enhanced preservation of the total adenine nucleotide pool and improved recovery of the energy charge in reperfused hearts. There was a trend towards increase in myocardial phosphocreatine by the end of re- perfusion in the A-12-I group; however this benefit did not reach statistical significance. At the end of reperfusion, myocardial lactate and lactate/pyruvate ratio were on average 5-fold lower in A-12-I treated hearts compared with control ones and did not differ significantly from the initial values. Therefore, improved cardiac dysfunction after I/R injury and less cell mem-brane damage induced by A-12 are associated with maintaining high energy phosphates, particularly ATP, in reperfused myocardium. Changes in energy metabolism may play a role in mechanisms of cardioprotection afforded by A-12 during I/R stress.
Cite this paper: nullPisarenko, O. , Shulzhenko, V. , Pelogeykina, Y. , Studneva, I. and Khatri, D. (2010) Apelin-12 improves metabolic and functional recovery of rat heart after global ischemia. Health, 2, 927-934. doi: 10.4236/health.2010.28137.

[1]   Verma, S., Fedak, P.W., Weisel, R. D., Butany, J., Rao, V. and Maitland, A. (2002) Fundamentals of reperfusion in-jury for the clinical cardiologist. Circulation, 105(20), 2332-2336.

[2]   Infanger, M., Faramarzi, S., Grosst, J., Kurth, E., Ulbrich, C. and Bauer J. (2007) Expression of vascular endothe-lial growth factor and receptor tyrosine kinases in cardiac ischemia/reperfusion injury. Cardiovascular Pathology, 16(5), 291-299.

[3]   Smith. C.C., Mocanu, M.M., Davidson, S. M., Wynne, A. M., Simpkin, J. C. and Yellon D. M. (2006) Leptin, the obesity-associated hormone, exhibits direct cardioprotec-tive effects. British Journal of Pharmacology, 149(1), 5-13.

[4]   Tatemoto, K., Hosoya, M., Habata, Y., Fujii, R., Kake-gawa, T., Zou, M. X., Kawamata, Y., Fukusumi, S., Hinuma, S., Kitada, C., Kurokawa, T., Onda, H. and Fu-jino, M. (1998) Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochemical and Biophysical Research Communications, 251(2), 471-476.

[5]   Boucher, J., Masri, B., Daviaud, D., Gesta S., Guigne, C. and Mazzucotelli, A. (2005) Apelin, a newly identified adipokine up-regulated by insulin and obesity. Endocri-nology, 146, 1764-1771.

[6]   Lee, D. K., Cheng, R., Nguyen, T., Fan, T., Kariyawasam, A. P., Liu, Y., Osmond, D. H., George, S. R. and O’Dowd, B.F. (2000) Characterization of apelin, the ligand for the APJ receptor. Journal of Neurochemistry, 74(1), 34-41.

[7]   Berry, M.F., Pirolli, T.J., Jayasankar, V., Burdick, J., Morine, K.J. and Gardner, T.J. (2004) Apelin has in vivo inotropic effects on normal and failing hearts. Circula-tion, 110(Supplement II), II187-II193.

[8]   Tatemoto, K., Takayama, K., Zou, M.X., Kumaki, I., Zhang, W. and Kumano, K. (2001) The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regulatory Peptides, 99(2-3), 87-92.

[9]   Chen, M.M., Ashley, E.A., Deng, D.X., Tsalenko, A., Deng, A. and Tabibiazar, R. (2003) Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction. Circulation, 108(12), 1432-1439.

[10]   Simpkin, J. C., Yellon, D. M., Davidson, S.M., Lim, S. Y., Wynne, A. M. and Smith, C. C. (2007) Apelin-13 and apelin-36 exhibit direct cardioprotective activity against ischemia-reperfusion injury. Basic Research in Cardiol-ogy, 102(6), 518-528.

[11]   Kleinz, M.J. and Baxter, G.F. (2008) Apelin reduces myocardial reperfusion injury independently of PI3K/Akt and P70S6 kinase. Regulatory Peptides, 146(1-3), 271- 277.

[12]   Zeng, X. J., Zhang, L. K., Wang, H. X., Lu, L. Q., Ma, L. Q. and Tang, C.S. (2009) Apelin protects heart against ischemia/reperfusion injury in rat. Peptides, 30(6), 1144- 1152.

[13]   Jia, Y. X., Lu, Z.F., Zhang, J., Pan, C. S., Yang, J.H. and Zhao, J. (2007) Apelin activates L-arginine/nitric oxide synthase/nitric oxide pathway in rat aortas. Peptides, 28(10), 2023-2029.

[14]   Masri, B., Lahlou, H., Mazarguil, H., Knibiehler, B. and Audigier, Y. (2002) Apelin (65-77) activates extracellular signal-regulated kinases via a PTX-sensitive G protein. Biochemical and Biophysical Research Communications, 290(1), 539-545.

[15]   Masri, B., Knibiehler, B. and Audigier, Y. (2005) Apelin signaling: A promising pathway from cloning to phar-macology. Cell Signaling, 17(4), 415-426.

[16]   Tsang, A., Hausenloy, D.J., Mocanu, M.M. and Yellon, D.M. (2004) Postconditioning: A form of “modified reperfusion” protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway. Circulation Research, 95(3), 230-232.

[17]   Kawamata, Y., Habata, Y. and Fukusumi, S. (2001) Mo-lecular properties of apelin: tissue distribution and re-ceptor binding. Biochimica et Biophysica Acta, 1538(2-3), 162-171.

[18]   Pisarenko, O. I., Shulzhenko, V. S. and Studneva, I.M. (1999) Metabolic effects of carbachol and ischaemic preconditioning in isolated rat heart. Clinical and Ex-perimental Pharmacology and Physiology, 26(1), 26-31.

[19]   Lamprecht, W. and Trautschold, I. (1974) Creatine phos- phate. Determination with CK, HK and G6P-DH. In: Bergmeyer, H. U., Ed., Methods of Enzymatic Analysis. Academic Press, New York, 1777-1781.

[20]   Jaworek, D., Gruber, W. and Bergmeyer, H.U. (1974) Adenosine-5’-diphosphate and adenosine-5’-monophos- phate. In: Bergmeyer, H. U., Ed., Methods of Enzymatic Analysis. Academic Press, New York, 2127-2131.

[21]   Bernt, E., Bergmeyer, H. U. and Mollering H. (1974) Creatine. In: Bergmeyer, H.U., Ed., Methods of Enzy-matic Analysis. Academic Press, New York, 1772-1776.

[22]   Gutman, I., Wahlenfeld, A.W.L. (1974) L-(+)-Lactate. Determination with LDH and NAD. In: Bergmeyer, H.U., Ed., Methods of Enzymatic Analysis. Academic Press, New York, 1464-1467.

[23]   Bucher, T., Czok, R., Lamprecht, W. and Latzko E. (1963) Pyruvate. In: Bergmeyer, H.U., Ed., Methods of enzy-matic analysis. Academic Press, New York, 2253-2259.

[24]   Bergmeyer, H.U. and Bernt, E. (1974) Lactate dehydro-genase. UV-assay with pyruvate and NADH. In: Berg-meyer, H.U., Ed., Methods of enzymatic analysis. Aca-demic Press, New York, 574-578.

[25]   Zeng, X.J., Wang, H.X., Lu, L.Q., Hao, G., Wang, X.Y. and Ma, L.Q. (2007) Effects and mechanisms of ape-lin-13 on ischemia/reperfusion injury in rat heart. Chini-cal Pharmacology Bull, 23(1), 82-85.

[26]   Ronkainen, V.P., Ronkainen, J.J. and Hanninen, S.L. (2007) Hypoxia inducible factor regulates the cardiac expression and secretion of apelin. Journal of the Fed-eration of American Societies for Experimental Biology, 21(8), 1821-1830.

[27]   Sheikh, A.Y., Chun, H.J. and Glassford, A.J. (2008) In vivo genetic profiling and cellular localization of apelin reveals a hypoxia-sensitive, endothelial centered pathway activated in ischemic heart failure. American Journal of Physiological Heart and Circulatory Physiology, 294(1), H88-H98.

[28]   Atluri, P., Morine, K.J. and Liao, G.P. (2007) Ischemic heart failure enhances endogenous myocardial apelin and A.P.J. receptor expression. Cellular and Molecular Biol-ogy Letter, 12(1), 127-138.

[29]   Jia, Y.X., Pan, C.S., Zhang, J., Geng, B., Zhao, J. and Gerns, H. (2006) Apelin protects myocardial injury in- duced by isoproterenol in rats. Regulatory Peptides, 133(1-3), 147-154.

[30]   Zhang, Z., Yu, B. and Tao, G.-Z. (2009) Apelin protects against cardiomyocyte apoptosis induced by glucose deprivation. Chiniese Medical Journal, 122(19), 2360- 2365.

[31]   Chandrasekaran, B., Dar, O. and McDonagh, T. (2008) The role of apelin in cardiovascular function and heart failure. European Journal of Heart Failure, 10(8), 725-732.

[32]   Smith, C.C., Mocanu, M.M. and Bowen, J. (2007) Tem-poral changes in myocardial salvage kinases during reperfusion following ischemia: Studies involving the cardioprotective adipocytokine apelin. Cardiovascular Drugs and Therapy, 21(6), 409-414.

[33]   Сheng, X., Cheng, X.S. and Pang, C.C. (2003) Venous dilator effect of apelin, an endogenous peptide ligand for the orphan APJ receptor, in conscious rats. European Journal of Pharmacology, 470(3), 171-175.

[34]   Rastaldo, R., Pagliaro, P., Cappello, S., Penna, C., Man-cardi, D., Westerhof, N. and Losano, G. (2005) Nitric oxide and cardiac function. Life Sciences, 81(10), 779- 793.

[35]   Shultz, R., Kelm, M. and Heusch, G. (2004) Nitric oxide in myocardial ischemia/reperfusion injury. Cardiovascu-lar Research, 61(3), 402-413.

[36]   Ferrari, R., Ceconi, C., Curello, S., Cargnoni, A., Alfieri, O., Pardini, A., Marzollo, P. and Visioli, O. (1991) Oxy-gen free radicals and myocardial damage: protective role of thiol-containing agents. The American Journal of Medicine, 91(3), 95S-105S.

[37]   Lipasti, J.A., Nevalainen, T.J., Alanen, K.A. and Tol-vanen, M.A. (1984) Anaerobic glycolysis and the devel-opment of ischaemic contracture in isolated rat heart. Cardiovascular Research, 18(3), 145-148.

[38]   Pisarenko, O.I., Lakomkin, V.L., Studneva, I.M., Ti-moshin, A.A., Kuzmin, A.I., Ruuge, E.K. and Kapelko, V.I. (1994) Allopurinol-enhanced postischemic recovery in the isolated rat heart involves repletion of high-energy phosphates. Biochemical Medicine and Metabolic Biol-ogy, 51(1), 16-26.

[39]   Rosen, E.D. and Spiegelman, B.M. (2006) Adipocytes as regulatord of energy balance and glucose homeostasis. Nature, 444(7120), 847-853.

[40]   Dray, C., Knauf, C., Daviaud, D., Waget, A., Boucher, J., Buleon, M., Cani, P.D., Attane, C. and Guigne, C. (2008) Apelin stimulates glucose utilization in normal and obese insulin-resistant mice. Cell Metabolism, 8(5), 437-445.

[41]   Li, J., Hu, X., Selvakumar, P., Russell, R.R., Cushman, S.W., Holman, G.D. and Young, L.H. (2004) Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle. American Journal of Physiology—Endocrinology Metabolism, 287(5), E834-E841.

[42]   Yue, P., Jin, H., Aillaud, M., Deng, A.C., Azuma, J., Asagami, T. and Kundu, R. K. (2010) Apelin is necessary for the maintenance of insulin sensitivity. American Journal of Physiology—Endocrinology Metabolism, 298(1), E59-E67.