The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지

Deficiency of iNOS Does Not Prevent Isoproterenol-induced Cardiac Hypertrophy in Mice

  • Cha, Hye-Na (Department of Physiology, College of Medicine, Yeungnam University) ;
  • Hong, Geu-Ru (Division of Cardiology, Department of Internal Medicine, College of Medicine, Yeungnam University) ;
  • Kim, Yong-Woon (Department of Physiology, College of Medicine, Yeungnam University) ;
  • Kim, Jong-Yeon (Department of Physiology, College of Medicine, Yeungnam University) ;
  • Dan, Jin-Myoung (Department of Orthopedic Surgery, Gumi CHA University Hospital) ;
  • Park, So-Young (Department of Physiology, College of Medicine, Yeungnam University)
  • Published : 2009.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

We investigated whether deficiency of inducible nitric oxide synthase (iNOS) could prevent isoproterenol-induced cardiac hypertrophy in iNOS knockout (KO) mice. Isoproterenol was continuously infused subcutaneously (15 mg/kg/day) using an osmotic minipump. Isoproterenol reduced body weight and fat mass in both iNOS KO and wild-type mice compared with saline-infused wild-type mice. Isoproterenol increased the heart weight in both iNOS KO and wild-type mice but there was no difference between iNOS KO and wild-type mice. Posterior wall thickness of left ventricle showed the same tendency with heart weight. Protein level of iNOS in the left ventricle was increased in isoproterenol-infused wild-type mice. The gene expression of interleukin-6 (IL-6) and transforming growth factor-${\beta}$ (TGF-${\beta}$) in isoproterenol-infused wild-type was measured at 2, 4, 24, and 48-hour and isoproterenol increased both IL-6 (2, 4, 24, and 48-hour) and TGF-${\beta}$ (4 and 24-hour). Isoproterenol infusion for 7 days increased the mRNA level of IL-6 and TGF-${\beta}$ in iNOS KO mice, whereas the gene expression in wild-type mice was not increased. Phosphorylated form of extracellular signal-regulated kinases (pERK) was also increased by isoproterenol at 2 and 4-hour but was not increased at 7 days after infusion in wild-type mice. However, the increased pERK level in iNOS KO mice was maintained even at 7 days after isoproterenol infusion. These results suggest that deficiency of iNOS does not prevent isoproterenol-induced cardiac hypertrophy and may have potentially harmful effects on cardiac hypertrophy.

Keywords

References

  1. Barry SP, Davidson SM, Townsend PA. Molecular regulation of cardiac hypertrophy. Int J Biochem Cell Biol 40: 2023−2039, 2008 https://doi.org/10.1016/j.biocel.2008.02.020
  2. oluyt MO, O'Neill L, Meredith AL, Bing OH, Brooks WW, Conrad CH, Crow MT, Lakatta EG. Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure. Marked upregulation of genes encoding extracellular matrix components. Circ Res 75: 23−32, 1994 https://doi.org/10.1161/01.RES.75.1.23
  3. Bueno OF, Molkentin JD. Involvement of extracellular signal- regulated kinases 1/2 in cardiac hypertrophy and cell death. Circ Res 91: 776−781, 2002 https://doi.org/10.1161/01.RES.0000038488.38975.1A
  4. Cha H. The Effect of iNOS deficiency on age-associated insulin resistance. MS Thesis, 2009
  5. Cmungrue IN, Gros R, You X, Pirani A, Azad A, Csont T, Schulz R, Butany J, Stewart DJ, Husain M. Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. J Clin Invest 109: 735−743, 2002
  6. Collins S, Surwit RS. The beta-adrenergic receptors and the control of adipose tissue metabolism and thermogenesis. Recent Prog Horm Res 56: 309−328, 2001 https://doi.org/10.1210/rp.56.1.309
  7. Funakoshi H, Kubota T, Kawamura N, Machida Y, Feldman AM, Tsutsui H, Shimokawa H, Takeshita A. Disruption of inducible nitric oxide synthase improves beta-adrenergic inotropic responsiveness but not the survival of mice with cytokine-induced cardiomyopathy. Circ Res 90: 959−965, 2002 https://doi.org/10.1161/01.RES.0000017632.83720.68
  8. Gardner DG, Chen S, Glenn DJ, Grigsby CL. Molecular biology of the natriuretic peptide system: implications for physiology and hypertension. Hypertension 49: 419−426, 2007 https://doi.org/10.1161/01.HYP.0000258532.07418.fa
  9. Godecke A, Molojavyi A, Heger J, Flogel U, Ding Z, Jacoby C, Schrader J. Myoglobin protects the heart from inducible nitric-oxide synthase (iNOS)-mediated nitrosative stress. J Biol Chem 278: 21761−21766, 2003 https://doi.org/10.1074/jbc.M302573200
  10. Greenwood JP, Scott EM, Stoker JB, Mary DA. Hypertensive left ventricular hypertrophy: relation to peripheral sympathetic drive. J Am Coll Cardiol 38: 1711−1717, 2001 https://doi.org/10.1016/S0735-1097(01)01600-X
  11. IKodama H, Fukuda K, Pan J, Sano M, Takahashi T, Kato T, Makino S, Manabe T, Murata M, Ogawa S. Significance of ERK cascade compared with JAK/STAT and PI3-K pathway in gp130-mediated cardiac hypertrophy. Am J Physiol Heart Circ Physiol 279: H1635−1644, 2000
  12. Imamura G, Bertelli AA, Bertelli A, Otani H, Maulik N, Das DK. Pharmacological preconditioning with resveratrol: an insight with iNOS knockout mice. Am J Physiol Heart Circ Physiol 282: H1996−2003, 2002
  13. Ji K, Minakawa M, Fukui K, Suzuki Y, Fukuda I. Increased superoxide radical with a decrease in vascular endothelial growth factor and inducible nitric oxide synthase level leads to the progression of left ventricular hypertrophy in a pressure- overload rat heart model. Ann Thorac Cardiovasc Surg 14: 210−217, 2008
  14. Kelly RA, Balligand JL, Smith TW. Nitric oxide and cardiac function. Circ Res 79: 363−380, 1996
  15. Krenek P, Kmecova J, Kucerova D, Bajuszova Z, Musil P, Gazova A, Ochodnicky P, Klimas J, Kyselovic J. Isoproterenol-induced heart failure in the rat is associated with nitric oxide-dependent functional alterations of cardiac function. Eur J Heart Fail 11: 140−146, 2009 https://doi.org/10.1093/eurjhf/hfn026
  16. Kundu S, Kumar M, Sen U, Mishra PK, Tyagi N, Metreveli N, Lominadze D, Rodriguez W, Tyagi SC. Nitrotyrosinylation, remodeling and endothelial-myocyte uncoupling in iNOS, cystathionine beta synthase (CBS) knockouts and iNOS/CBS double knockout mice. J Cell Biochem 106: 119−126, 2009 https://doi.org/10.1002/jcb.21982
  17. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the framingham heart study. N Engl J Med 322: 1561−1566, 1990 https://doi.org/10.1056/NEJM199005313222203
  18. Li RK, Li G, Mickle DA, Weisel RD, Merante F, Luss H, Rao V, Christakis GT, Williams WG. Overexpression of transforming growth factor-beta1 and insulin-like growth factor-I in patients with idiopathic hypertrophic cardiomyopathy. Circulation 96: 874−881, 1997 https://doi.org/10.1161/01.CIR.96.3.874
  19. Mikaelian I, Coluccio D, Morgan KT, Johnson T, Ryan AL, Rasmussen E, Nicklaus R, Kanwal C, Hilton H, Frank K, Fritzky L, Wheeldon EB. Temporal gene expression profiling indicates early up-regulation of interleukin-6 in isoproterenol-induced myocardial necrosis in rat. Toxicol Pathol 36: 256−264, 2008 https://doi.org/10.1177/0192623307312696
  20. Osadchii OE. Cardiac hypertrophy induced by sustained beta- adrenoreceptor activation: pathophysiological aspects. Heart Fail Rev 12: 66−86, 2007 https://doi.org/10.1007/s10741-007-9007-4
  21. Pauschinger M, Knopf D, Petschauer S, Doerner A, Poller W, Schwimmbeck PL, Kuhl U, Schultheiss HP. Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio. Circulation 99: 2750−2756, 1999 https://doi.org/10.1161/01.CIR.99.21.2750
  22. Pelat M, Verwaerde P, Galitzky J, Lafontan M, Berlan M, Senard JM, Montastruc JL. High isoproterenol doses are required to activate beta3-adrenoceptor-mediated functions in dogs. J Pharmacol Exp Ther 304: 246−253, 2003 https://doi.org/10.1124/jpet.102.040691
  23. Rajabi M, Kassiotis C, Razeghi P, Taegtmeyer H. Return to the fetal gene program protects the stressed heart: a strong hypothesis. Heart Fail Rev 12: 331−343, 2007 https://doi.org/10.1007/s10741-007-9034-1
  24. Schlaich MP, Kaye DM, Lambert E, Sommerville M, Socratous F, Esler MD. Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Circulation 108: 560−565, 2003 https://doi.org/10.1161/01.CIR.0000081775.72651.B6
  25. Strand AH, Gudmundsdottir H, Os I, Smith G, Westheim AS, Bjornerheim R, Kjeldsen SE. Arterial plasma noradrenaline predicts left ventricular mass independently of blood pressure and body build in men who develop hypertension over 20 years. J Hypertens 24: 905−913, 2006 https://doi.org/10.1097/01.hjh.0000222761.07477.7b
  26. Szabo J, Csaky L, Szegi J. Experimental cardiac hypertrophy induced by isoproterenol in the rat. Acta Physiol Acad Sci Hung 46: 281−285, 1975
  27. Tanaka T, Kanda T, Itoh T, Tsugawa H, Takekoshi N, Yamakawa J, Kurimoto M, Kurabayashi M. Increased cardiac weight in interleukin-6 transgenic mice with viral infection accompanies impaired expression of natriuretic peptide genes. Res Commun Mol Pathol Pharmacol 110: 275−283, 2001
  28. Tsuchiya K, Sakai H, Suzuki N, Iwashima F, Yoshimoto T, Shichiri M, Hirata Y. Chronic blockade of nitric oxide synthesis reduces adiposity and improves insulin resistance in high fat-induced obese mice. Endocrinology 148: 4548−4556, 2007 https://doi.org/10.1210/en.2006-1371
  29. Villarreal FJ, Dillmann WH. Cardiac hypertrophy-induced changes in mRNA levels for TGF-beta 1, fibronectin, and collagen. Am J Physiol 262: H1861−1866, 1992
  30. Wang T, Yan M, Li J, Zheng X. The role of iNOS-derived NO in the antihypertrophic actions of B-type natriuretic peptide in neonatal rat cardiomyocytes. Mol Cell Biochem 302: 169−177, 2007 https://doi.org/10.1007/s11010-007-9438-1
  31. Xi L, Jarrett NC, Hess ML, Kukreja RC. Essential role of inducible nitric oxide synthase in monophosphoryl lipid A-induced late cardioprotection: evidence from pharmacological inhibition and gene knockout mice. Circulation 99: 2157−2163, 1999
  32. Zhang GX, Kimura S, Nishiyama A, Shokoji T, Rahman M, Yao L, Nagai Y, Fujisawa Y, Miyatake A, Abe Y. Cardiac oxidative stress in acute and chronic isoproterenol-infused rats. Cardiovasc Res 65: 230−238, 2005 https://doi.org/10.1016/j.cardiores.2004.08.013
  33. Zhang J, Knapton A, Lipshultz SE, Weaver JL, Herman EH. Isoproterenol-induced cardiotoxicity in sprague-dawley rats: correlation of reversible and irreversible myocardial injury with release of cardiac troponin T and roles of iNOS in myocardial injury. Toxicol Pathol 36: 277−278, 2008 https://doi.org/10.1177/0192623307313010
  34. Zhang P, Xu X, Hu X, van Deel ED, Zhu G, Chen Y. Inducible nitric oxide synthase deficiency protects the heart from systolic overload-induced ventricular hypertrophy and congestive heart failure. Circ Res 100: 1089−1098, 2007 https://doi.org/10.1161/01.RES.0000264081.78659.45
  35. Zingarelli B, Hake PW, Yang Z, O'Connor M, Denenberg A, Wong HR. Absence of inducible nitric oxide synthase modulates early reperfusion-induced NF-kappaB and AP-1 activation and enhances myocardial damage. Faseb J 16: 327−342, 2002 https://doi.org/10.1096/fj.01-0533com