Nitric oxide synthase mediates the apelin-induced improvement of myocardial postischemic metabolic and functional recovery
Affiliation(s)
Laboratory for Myocardial Metabolism, Russian Cardiology Research-and-Production Complex, Moscow, Russia.
Laboratory for Myocardial Metabolism, Russian Cardiology Research-and-Production Complex, Moscow, Russia.
ABSTRACT
The adipocytokine apelin is capable to reduce myocardial ischemia/reperfusion injury in rodents. Cardioprotective activity of apelin may be attributed to upregulation of endothelial nitric oxide synthase (eNOS). This study was designed to examine metabolic and functional effects of a synthesized 12 C-terminal residue of apelin (A-12) and NG-nitro-L-arginine methyl ester (L-NAME), a non-selective eNOS inhibitor, in isolated working rat hearts subjected to global ischemia. Preischemic infusion of A-12 increased recovery of cardiac function during reperfusion compared with control and resulted in enhanced restoration of myocardial ATP, adenine nucleotide pool, phosphocreatine and reduction of myocardial lactate and lactate/pyruvate ratio. Coadministration of A-12 and L-NAME aggravated recovery of coronary flow and cardiac function compared with these indices after A-12 treatment. Cardiac dysfunction was associated with increase in lactate dehydrogenase release in myocardial effluent, reduction of glucose oxidation and abolishment of augmented restoration of high energy phosphates. The results clearly demonstrate involvement of NOS-dependent mechanisms in cardioprotection afforded by apelin.
The adipocytokine apelin is capable to reduce myocardial ischemia/reperfusion injury in rodents. Cardioprotective activity of apelin may be attributed to upregulation of endothelial nitric oxide synthase (eNOS). This study was designed to examine metabolic and functional effects of a synthesized 12 C-terminal residue of apelin (A-12) and NG-nitro-L-arginine methyl ester (L-NAME), a non-selective eNOS inhibitor, in isolated working rat hearts subjected to global ischemia. Preischemic infusion of A-12 increased recovery of cardiac function during reperfusion compared with control and resulted in enhanced restoration of myocardial ATP, adenine nucleotide pool, phosphocreatine and reduction of myocardial lactate and lactate/pyruvate ratio. Coadministration of A-12 and L-NAME aggravated recovery of coronary flow and cardiac function compared with these indices after A-12 treatment. Cardiac dysfunction was associated with increase in lactate dehydrogenase release in myocardial effluent, reduction of glucose oxidation and abolishment of augmented restoration of high energy phosphates. The results clearly demonstrate involvement of NOS-dependent mechanisms in cardioprotection afforded by apelin.
Cite this paper
Pisarenko, O. , Pelogeykina, Y. , Shulzhenko, V. and Studneva, I. (2012) Nitric oxide synthase mediates the apelin-induced improvement of myocardial postischemic metabolic and functional recovery. Open Journal of Molecular and Integrative Physiology, 2, 1-7. doi: 10.4236/ojmip.2012.21001.
Pisarenko, O. , Pelogeykina, Y. , Shulzhenko, V. and Studneva, I. (2012) Nitric oxide synthase mediates the apelin-induced improvement of myocardial postischemic metabolic and functional recovery. Open Journal of Molecular and Integrative Physiology, 2, 1-7. doi: 10.4236/ojmip.2012.21001.
References
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(1998) Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochemical and Biophysical Research Communications, 251, 471-476. doi:10.1006/bbrc.1998.9489 [7] Berry, M.F., Pirolli, T.J., Jayasankar, V., et al. (2004) Apelin has in vivo inotropic effects on normal and failing hearts. Circulation, 110, II187-II193. doi:10.1161/01.CIR.0000138382.57325.5c [8] Chen, M.M., Ashley, E.A., Deng, D.X., et al. (2003) Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction. Circulation, 108, 1432-1439. doi:10.1161/01.CIR.0000091235.94914.75 [9] Japp, A.G., Cruden, N.L., Barnes, G., et al. (2010) Acute cardiovascular effects of apelin in humans. Potential role in patients with chronic heart failure. Circulation, 12, 1818-1827. doi:10.1161/CIRCULATIONAHA.109.911339 [10] Simpkin, J.C., Yellon, D.M., Davidson, S.M., et al. (2007) Apelin-13 and apelin-36 exhibit direct cardioprotective activity against ischemia-reperfusion injury. Basic Research in Cardiology, 102, 518-528. doi:10.1007/s00395-007-0671-2 [11] Kleinz, M.J. and Baxter, G.F. (2008) Apelin reduces myocardial reperfusion injury independently of PI3K/Akt and P70S6 kinase. Regulatory Peptides, 146, 271-277. doi:10.1016/j.regpep.2007.10.002 [12] Zeng, X.J., Zhang, L.K., Wang, H.X., et al. (2009) Apelin protects heart against ischemia/reperfusion injury in rat. Peptides, 30, 1144-1152. doi:10.1016/j.peptides.2009.02.010 [13] Zhang, Z., Yu, B. and Tao, G. (2009) Apelin protects against cardiomyocyte apoptosis induced by glucose deprivation. Chinese Medical Journal, 122, 2360-2365. [14] Masri, B., Knibiehler, B. and Audigier, Y. (2005) Apelin signalling: A promising pathway from cloning to pharmacology. Cellular Signaling, 17, 415-426. doi:10.1016/j.cellsig.2004.09.018 [15] Smith, C.C., Mocanu, M.M., Bowen, J., et al. (2007) Temporal changes in myocardial salvage kinases during reperfusion following ischemia: Studies involving the cardioprotective adipocytokine apelin. Cardiovascular Drugs and Therapy, 21, 409-414. doi:10.1007/s10557-007-6054-y [16] Rastaldo, R., Cappello, S., Folino, A. and Losano, G. (2010) Effect of apelin—Apelin receptor system in postischaemic myocardial protection: A pharmacological postconditioning tool? Antioxidants and Redox Signaling, 14, 909-922. doi:10.1089/ars.2010.3355 [17] Datta, S.R., Dudek, H., Tao, X., et al. (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell, 91, 231-241. doi:10.1016/S0092-8674(00)80405-5 [18] Shultz, R., Kelm, M. and Heusch, G. (2004) Nitric oxide in myocardial ischemia/reperfusion injury. Cardiovascular Research, 61, 402-413. doi:10.1016/j.cardiores.2003.09.019 [19] Balakirev, M.Y., Khramtsov, V.V. and Zimmer, G. (1997) Modulation of the mitochondrial permeability transition by nitric oxide. European Journal of Biochemistry, 246, 710-718. doi:10.1111/j.1432-1033.1997.00710.x [20] Rastaldo, R., Cappello, S., Folino, A., et al. (2011) Apelin-13 limits infarct size and improves cardiac postischemic mechanical recovery only if given after ischemia. American Journal of Physiology, 300, H2308-Н2315. doi:10.1152/ajpheart.01177.2010 [21] Pisarenko, O.I., Shulzhenko, V.S., Pelogeykina, Y.A., Studneva, I.M. and Khatri, D.N. (2010) Apelin-12 improves metabolic and functional recovery of rat heart after global ischemia. Health, 2, 927-934. doi:10.4236/health.2010.28137 [22] Langelaan, D.N. and Rainey, J.K. (2009) Headgroup— Dependent membrane catalysis of apelin-receptor interactions is likely. The Journal of Physical Chemistry, 113, 10465-10471. doi:10.1021/jp904562q [23] Fan, X., Zhou, N., Zhang, X., et al. (2003) Structural and functional study of the apelin-13 peptide, an endogenous ligand of the HIV-1 coreceptor, APJ. Biochemistry, 42, 10163-10168. doi:10.1021/bi030049s [24] Andelová, E., Barteková, M., Pancza, D. and Ravingerová, T. (2005) The role of No in ischemia/reperfusion injury in isolated rat heart. General Physiology and Biophysics, 24, 411-426. [25] Lamprecht, W. and Trautschold, I. (1974) Creatine phosphate. Determination with CK, HK and G6P-DH. In: Bergmeyer, H.U. Ed., Methods of enzymatic analysis, Academic Press, New York, 1777-1781. [26] Jaworek, D., Gruber, W. and Bergmeyer, H.U. (1974) Adenosine-5’-diphosphate and adenosine-5’-monopho sphate. In: Bergmeyer, H.U., Ed., Methods of Enzymatic Analysis, Academic Press, New York, 2127-2131. [27] Bernt, E., Bergmeyer, H.U. and Mollering, H. (1974) Creatine. In: Bergmeyer, H.U., Ed., Methods of Enzymatic Analysis, Academic Press, New York, 1772-1776. [28] Gutman, I. and Wahlenfeld, A.W.L. (1963) L-(+)-lactate. determination with LDH and NAD. In: Bergmeyer, H.U., Ed., Methods of Enzymatic Analysis, Academic Press, New York, 1464-1467. [29] Bucher, T., Czok, R., Lamprecht, W., et al. (1963) Pyruvate. In: Bergmeyer, H.U., Ed., Methods of enzymatic analysis, Academic Press, New York, 2253-2259. [30] Bergmeyer, H.U. and Bernt, E. (1974) Lactate dehydrogenase. UV-assay with pyruvate and NADH. In: Bergmeyer, H.U., Ed., Methods of Enzymatic Analysis, Academic Press, New York, 574-578. [31] Dray, C., Knauf, C., Daviaud, D., et al. (2008) Apelin stimulates glucose utilization in normal and obese insulin-resistant mice. Cell Metabolism, 8, 437-445. doi:10.1016/j.cmet.2008.10.003 [32] Li, J., Hu, X., Selvakumar, P., et al. (2004) Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle. American Journal of Physiology, 287, E834-E841. doi:10.1152/ajpendo.00234.2004 [33] Yue, P., Jin, H., Aillaud, M., et al. (2010) Apelin is necessary for the maintenance of insulin sensitivity. American Journal of Physiology, 298, E59-E67. doi:10.1152/ajpendo.00385.2009 [34] Lee, D.K., Cheng, R., Nguyen, T., et al. (2000) Characterization of apelin, the ligand for the APJ receptor. Journal of Neurochemistry, 74, 34-41. doi:10.1046/j.1471-4159.2000.0740034.x [35] 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, 171-175. doi:10.1016/S0014-2999(03)01821-1 [36] Tatemoto, K., Takayama, K., Zou, M.X., et al. (2001) The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regulatory Peptides, 99, 87-92. doi:10.1016/S0167-0115(01)00236-1 [37] Ishida, J., Hashimoto, T., Hashimoto, Y., et al. (2004) Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo. The Journal of Biological Chemistry, 279, 26274-26279. doi:10.1074/jbc.M404149200 [38] Masri, B., Morin, N., Pedebernade, L., Knibiehler, B. and Audigier, Y. (2006) The apelin receptor is coupled to Gi1 or Gi2 protein and is differentially desensitized by apelin fragments. The Journal of Biological Chemistry, 281, 18317-18326. doi:10.1074/jbc.M600606200 [39] Zhong, J.C., Yu, X.Y., Huang, Y., et al. (2007) Apelin modulates aortic vascular tone via endothelial nitric oxide synthase phosphorylation pathway in diabetic mice. Cardiovascular Research, 74, 388-395. doi:10.1016/j.cardiores.2007.02.002 [40] Chun, H.J., Ali, Z.A., Kojima, Y., et al. (2008) Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis. Journal of Clinical Investigation, 118, 3343-3354. [41] Jia, Y.X., Lu, Z.F., Zhang, J., et al. (2007) Apelin activates L-arginine/nitric oxide synthase/nitric oxide pathway in rat aortas. Peptides, 28, 2023-2029. doi:10.1016/j.peptides.2007.07.016 [42] Wink, D.A., Hanbauer, I., Krishna, M.C., et al. (1993) Nitric oxide protects against cellular damage and cytotoxicity from reactive oxygen species. Proceedings of the National Academy of Sciences of USA, 90, 9813-9817. doi:10.1073/pnas.90.21.9813
[1] Gross, G.J., Kersten, J.R. and Warltier, D.C. (1999) Mechanisms of postischemic contractile dysfunction. Annual Thoracic Surgery, 68, 1898-1904. doi:10.1016/S0003-4975(99)01035-8 [2] Przyklenk, K. (2001) Pharmacologic treatment of the stunned myocardium: The concepts and the challenges. Coronary Artery Disease, 12, 363-369. doi:10.1097/00019501-200108000-00005 [3] Pisarenko, O.I., Lepilin, M.G. and Ivanov, V.E. (1986) Cardiac metabolism and performance during L-glutamic acid infusion in postoperative cardiac failure. Clinical Science, 70, 7-12. [4] Verma, S., Fedak, P.W.M. and Weisel, R.D. (2002) Fundamentals of reperfusion injury for the clinical cardiologist. Circulation, 105, 2332-2336. doi:10.1161/01.CIR.0000016602.96363.36 [5] Kleinz, M.J. and Davenport, A.P. (2005) Emerging roles of apelin in biology and medicine. Pharmacology & Therapeutics, 107, 198-211. doi:10.1016/j.pharmthera.2005.04.001 [6] Tatemoto, K., Hosoya, M., Habata, Y., et al. (1998) Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochemical and Biophysical Research Communications, 251, 471-476. doi:10.1006/bbrc.1998.9489 [7] Berry, M.F., Pirolli, T.J., Jayasankar, V., et al. (2004) Apelin has in vivo inotropic effects on normal and failing hearts. Circulation, 110, II187-II193. doi:10.1161/01.CIR.0000138382.57325.5c [8] Chen, M.M., Ashley, E.A., Deng, D.X., et al. (2003) Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction. Circulation, 108, 1432-1439. doi:10.1161/01.CIR.0000091235.94914.75 [9] Japp, A.G., Cruden, N.L., Barnes, G., et al. (2010) Acute cardiovascular effects of apelin in humans. Potential role in patients with chronic heart failure. Circulation, 12, 1818-1827. doi:10.1161/CIRCULATIONAHA.109.911339 [10] Simpkin, J.C., Yellon, D.M., Davidson, S.M., et al. (2007) Apelin-13 and apelin-36 exhibit direct cardioprotective activity against ischemia-reperfusion injury. Basic Research in Cardiology, 102, 518-528. doi:10.1007/s00395-007-0671-2 [11] Kleinz, M.J. and Baxter, G.F. (2008) Apelin reduces myocardial reperfusion injury independently of PI3K/Akt and P70S6 kinase. Regulatory Peptides, 146, 271-277. doi:10.1016/j.regpep.2007.10.002 [12] Zeng, X.J., Zhang, L.K., Wang, H.X., et al. (2009) Apelin protects heart against ischemia/reperfusion injury in rat. Peptides, 30, 1144-1152. doi:10.1016/j.peptides.2009.02.010 [13] Zhang, Z., Yu, B. and Tao, G. (2009) Apelin protects against cardiomyocyte apoptosis induced by glucose deprivation. Chinese Medical Journal, 122, 2360-2365. [14] Masri, B., Knibiehler, B. and Audigier, Y. (2005) Apelin signalling: A promising pathway from cloning to pharmacology. Cellular Signaling, 17, 415-426. doi:10.1016/j.cellsig.2004.09.018 [15] Smith, C.C., Mocanu, M.M., Bowen, J., et al. (2007) Temporal changes in myocardial salvage kinases during reperfusion following ischemia: Studies involving the cardioprotective adipocytokine apelin. Cardiovascular Drugs and Therapy, 21, 409-414. doi:10.1007/s10557-007-6054-y [16] Rastaldo, R., Cappello, S., Folino, A. and Losano, G. (2010) Effect of apelin—Apelin receptor system in postischaemic myocardial protection: A pharmacological postconditioning tool? Antioxidants and Redox Signaling, 14, 909-922. doi:10.1089/ars.2010.3355 [17] Datta, S.R., Dudek, H., Tao, X., et al. (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell, 91, 231-241. doi:10.1016/S0092-8674(00)80405-5 [18] Shultz, R., Kelm, M. and Heusch, G. (2004) Nitric oxide in myocardial ischemia/reperfusion injury. Cardiovascular Research, 61, 402-413. doi:10.1016/j.cardiores.2003.09.019 [19] Balakirev, M.Y., Khramtsov, V.V. and Zimmer, G. (1997) Modulation of the mitochondrial permeability transition by nitric oxide. European Journal of Biochemistry, 246, 710-718. doi:10.1111/j.1432-1033.1997.00710.x [20] Rastaldo, R., Cappello, S., Folino, A., et al. (2011) Apelin-13 limits infarct size and improves cardiac postischemic mechanical recovery only if given after ischemia. American Journal of Physiology, 300, H2308-Н2315. doi:10.1152/ajpheart.01177.2010 [21] Pisarenko, O.I., Shulzhenko, V.S., Pelogeykina, Y.A., Studneva, I.M. and Khatri, D.N. (2010) Apelin-12 improves metabolic and functional recovery of rat heart after global ischemia. Health, 2, 927-934. doi:10.4236/health.2010.28137 [22] Langelaan, D.N. and Rainey, J.K. (2009) Headgroup— Dependent membrane catalysis of apelin-receptor interactions is likely. The Journal of Physical Chemistry, 113, 10465-10471. doi:10.1021/jp904562q [23] Fan, X., Zhou, N., Zhang, X., et al. (2003) Structural and functional study of the apelin-13 peptide, an endogenous ligand of the HIV-1 coreceptor, APJ. Biochemistry, 42, 10163-10168. doi:10.1021/bi030049s [24] Andelová, E., Barteková, M., Pancza, D. and Ravingerová, T. (2005) The role of No in ischemia/reperfusion injury in isolated rat heart. General Physiology and Biophysics, 24, 411-426. [25] Lamprecht, W. and Trautschold, I. (1974) Creatine phosphate. Determination with CK, HK and G6P-DH. In: Bergmeyer, H.U. Ed., Methods of enzymatic analysis, Academic Press, New York, 1777-1781. [26] Jaworek, D., Gruber, W. and Bergmeyer, H.U. (1974) Adenosine-5’-diphosphate and adenosine-5’-monopho sphate. In: Bergmeyer, H.U., Ed., Methods of Enzymatic Analysis, Academic Press, New York, 2127-2131. [27] Bernt, E., Bergmeyer, H.U. and Mollering, H. (1974) Creatine. In: Bergmeyer, H.U., Ed., Methods of Enzymatic Analysis, Academic Press, New York, 1772-1776. [28] Gutman, I. and Wahlenfeld, A.W.L. (1963) L-(+)-lactate. determination with LDH and NAD. In: Bergmeyer, H.U., Ed., Methods of Enzymatic Analysis, Academic Press, New York, 1464-1467. [29] Bucher, T., Czok, R., Lamprecht, W., et al. (1963) Pyruvate. In: Bergmeyer, H.U., Ed., Methods of enzymatic analysis, Academic Press, New York, 2253-2259. [30] Bergmeyer, H.U. and Bernt, E. (1974) Lactate dehydrogenase. UV-assay with pyruvate and NADH. In: Bergmeyer, H.U., Ed., Methods of Enzymatic Analysis, Academic Press, New York, 574-578. [31] Dray, C., Knauf, C., Daviaud, D., et al. (2008) Apelin stimulates glucose utilization in normal and obese insulin-resistant mice. Cell Metabolism, 8, 437-445. doi:10.1016/j.cmet.2008.10.003 [32] Li, J., Hu, X., Selvakumar, P., et al. (2004) Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle. American Journal of Physiology, 287, E834-E841. doi:10.1152/ajpendo.00234.2004 [33] Yue, P., Jin, H., Aillaud, M., et al. (2010) Apelin is necessary for the maintenance of insulin sensitivity. American Journal of Physiology, 298, E59-E67. doi:10.1152/ajpendo.00385.2009 [34] Lee, D.K., Cheng, R., Nguyen, T., et al. (2000) Characterization of apelin, the ligand for the APJ receptor. Journal of Neurochemistry, 74, 34-41. doi:10.1046/j.1471-4159.2000.0740034.x [35] 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, 171-175. doi:10.1016/S0014-2999(03)01821-1 [36] Tatemoto, K., Takayama, K., Zou, M.X., et al. (2001) The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regulatory Peptides, 99, 87-92. doi:10.1016/S0167-0115(01)00236-1 [37] Ishida, J., Hashimoto, T., Hashimoto, Y., et al. (2004) Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo. The Journal of Biological Chemistry, 279, 26274-26279. doi:10.1074/jbc.M404149200 [38] Masri, B., Morin, N., Pedebernade, L., Knibiehler, B. and Audigier, Y. (2006) The apelin receptor is coupled to Gi1 or Gi2 protein and is differentially desensitized by apelin fragments. The Journal of Biological Chemistry, 281, 18317-18326. doi:10.1074/jbc.M600606200 [39] Zhong, J.C., Yu, X.Y., Huang, Y., et al. (2007) Apelin modulates aortic vascular tone via endothelial nitric oxide synthase phosphorylation pathway in diabetic mice. Cardiovascular Research, 74, 388-395. doi:10.1016/j.cardiores.2007.02.002 [40] Chun, H.J., Ali, Z.A., Kojima, Y., et al. (2008) Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis. Journal of Clinical Investigation, 118, 3343-3354. [41] Jia, Y.X., Lu, Z.F., Zhang, J., et al. (2007) Apelin activates L-arginine/nitric oxide synthase/nitric oxide pathway in rat aortas. Peptides, 28, 2023-2029. doi:10.1016/j.peptides.2007.07.016 [42] Wink, D.A., Hanbauer, I., Krishna, M.C., et al. (1993) Nitric oxide protects against cellular damage and cytotoxicity from reactive oxygen species. Proceedings of the National Academy of Sciences of USA, 90, 9813-9817. doi:10.1073/pnas.90.21.9813