Inhibition of inducible nitric oxide synthase (iNOS) by simvastatin attenuates cardiac hypertrophy in rats

• Autorzy: Ahmed A.M.
• Języki publikacji: EN

Abstrakty

EN

Background:The left ventricular hypertrophy (LVH) occurs in response to the haemodynamic overload in some physiological and pathological conditions. This study was designed to investigate the possible cardioprotective effect of simvastatin (SIM) treatment against isoproterenol (ISO)-induced LVH and the probable underlying mechanism in adult male Wistar rats. Materials and methods: Animals were allocated into four groups. Rats of control group received normal saline orally for 30 days and intraperitoneally for the last 7 days. Rats of SIM group received SIM orally (10 mg/kg/day in saline) for 30 days. Rats of ISO group received normal saline orally for 30 days and ISO intraperitoneally (5 mg/kg) for the last 7 days to induce LVH. Rats of ISO/SIM group received SIM for 30 days and ISO intraperitoneally for the last 7 days. At the end of the experiment, all animals were sacrificed by cervical decapitation under anaesthesia. Truncal blood was collected and serum was separated and used for biochemical assay. The heart was dissected and processed for histological and immunohistochemical studies. Results: The results of the present study confirmed the ISO-induced myocardial lesions including significant increase of heart weight (HW), heart weight/body weight (HW/BW) ratio, LVH, interstitial myocardial fibrosis (increased collagen types I and III), inflammatory cellular infiltration, necrosis of cardiomyocytes, and increased expression of inducible nitric oxide synthase (iNOS) and thioredoxin in cardiomyocytes. These changes were accompanied by significant increase in serum levels of troponin-T, creatine phosphokinase-MB (CPK-MB), tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Co-administration of SIM to ISO-injected rats significantly reduced all these cardiac changes and serum biochemical markers in addition to marked depletion of iNOS and thioredoxin expression in cardiomyocytes. Conclusions: It is concluded that SIM co-administration attenuated ISO-induced cardiac lesions including LVH by inhibiting iNOS expression in cardiomyocytes. (Folia Morphol 2017; 76, 1: 15–27)

• Wydawca: -
• Czasopismo: Folia Morphologica
• Rocznik: 2017
• Tom: 76
• Numer: 1
• Opis fizyczny: p.15-27,fig.,ref.

Twórcy

autor

Ahmed A.M.

• Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia

Bibliografia

• 1. Abrahams C, Janicki JS, Weber KT. Myocardial hypertrophy in Macaca fascicularis. Structural remodeling of the collagen matrix. Lab Invest. 1987; 56(6): 676–683, indexed in Pubmed: 2955170.
• 2. Arnér ES, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem. 2000; 267(20): 6102–6109, doi:10.1046/j.1432-1327.2000.01701.x, indexed in Pubmed: 11012661.
• 3. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol. 1996; 271(5 Pt 1): C1424–C1437, doi:10.1136/thx.2004.038471, indexed in Pubmed: 8944624.
• 4. Benjamin IJ, Jalil JE, Tan LB, et al. Isoproterenol-induced myocardial fibrosis in relation to myocyte necrosis. Circ Res. 1989; 65(3): 657–670, doi:10.1161/01.res.65.3.657, indexed in Pubmed: 2527639.
• 5. Boluyt MO, Long X, Eschenhagen T, et al. Isoproterenol infusion induces alterations in expression of hypertrophyassociated genes in rat heart. Am J Physiol. 1995; 269(2 Pt 2): H638–H647, indexed in Pubmed: 7653628.
• 6. Bradbury P, Rae K. Connective tissues and stains. In: Bancroft J, Stevens A, editors. Theory and Practice of Histological Techqniues. 4th ed. Churchill Livingstone, London, New York, Toronto. 1999: pp. 113–138.
• 7. Brooks WW, Conrad CH. Isoproterenol-induced myocardial injury and diastolic dysfunction in mice: structural and functional correlates. Comp Med. 2009; 59(4): 339–343, indexed in Pubmed: 19712573.
• 8. Chen YQ, Zhao LY, Zhang WZ, et al. Simvastatin reverses cardiomyocyte hypertrophy via the upregulation of phosphatase and tensin homolog expression. Exp Ther Med. 2015; 10(2): 797–803, doi: 10.3892/etm.2015.2550, indexed in Pubmed: 26622396.
• 9. Choudhary R, Mishra KP, Subramanyam C. Prevention of isoproterenol-induced cardiac hypertrophy by eugenol, an antioxidant. Indian J Clin Biochem. 2006; 21(2): 107–113, doi: 10.1007/BF02912923, indexed in Pubmed: 23105625.
• 10. Csont T, Viappiani S, Sawicka J, et al. The involvement of superoxide and iNOS-derived NO in cardiac dysfunction induced by pro-inflammatory cytokines. J Mol Cell Cardiol. 2005; 39(5): 833–840, doi: 10.1016/j.yjmcc.2005.07.010, indexed in Pubmed: 16171809.
• 11. D’Armiento J. Matrix metalloproteinase disruption of the extracellular matrix and cardiac dysfunction. Trends Cardiovasc. Med. 2002; 12(3): 97–101, doi: 10.1016/s1050-1738(01)00160-8, indexed in Pubmed: 12007733.
• 12. Doering CW, Jalil JE, Janicki JS, et al. Collagen network remodelling and diastolic stiffness of the rat left ventricle with pressure overload hypertrophy. Cardiovasc Res. 1988; 22(10): 686–695, doi: 10.1093/cvr/22.10.686, indexed in Pubmed: 2978464.
• 13. Escames G, Khaldy H, León J, et al. Changes in iNOS activity, oxidative stress and melatonin levels in hypertensive patients treated with lacidipine. J Hypertens. 2004; 22(3): 629–635, doi: 10.1097/00004872-200403000-00027, indexed in Pubmed: 15076170.
• 14. Ferdinandy P, Danial H, Ambrus I, et al. Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res. 2000; 87(3): 241–247, doi: 10.1161/01.res.87.3.241, indexed in Pubmed: 10926876.
• 15. Gealekman O, Abassi Z, Rubinstein I, et al. Role of myocardial inducible nitric oxide synthase in contractile dysfunction and beta-adrenergic hyporesponsiveness in rats with experimental volume-overload heart failure. Circulation. 2002; 105(2): 236–243, doi: 10.1161/hc0202.102015, indexed in Pubmed: 11790707.
• 16. Gradman AH, Alfayoumi F. From left ventricular hypertrophy to congestive heart failure: management of hypertensive heart disease. Prog Cardiovasc Dis. 2006; 48(5): 326–341, doi: 10.1016/j.pcad.2006.02.001, indexed in Pubmed: 16627048.
• 17. Guzy PM. Creatine phosphokinase-MB (CPK-MB) and the diagnosis of myocardial infarction. West J Med. 1977; 127(6): 455–460, doi:10.1056/nejm199503023320914, indexed in Pubmed: 339548.
• 18. Habib FM, Springall DR, Davies GJ, et al. Tumour necrosis factor and inducible nitric oxide synthase in dilated cardiomyopathy. Lancet. 1996; 347(9009): 1151–1155, doi: 10.1016/s0140-6736(96)90610-8, indexed in Pubmed: 8609750.
• 19. Haywood GA, Tsao PS, von der Leyen HE, et al. Expression of inducible nitric oxide synthase in human heart failure. Circulation. 1996; 93(6): 1087–1094, doi: 10.1161/01.cir.93.6.1087, indexed in Pubmed: 8653828.
• 20. Henderson BC, Tyagi N, Ovechkin A, et al. Oxidative remodeling in pressure overload induced chronic heart failure. Eur J Heart Fail. 2007; 9(5): 450–457, doi: 10.1016/j.ejheart.2006.12.008, indexed in Pubmed: 17306621.
• 21. Huang XY, Chen CX, Zhang XM, et al. Effects of ethanolic extract from Radix Scrophulariae on ventricular remodeling in rats. Phytomedicine. 2012; 19(3-4): 193–205, doi: 10.1016/j.phymed.2011.09.079, indexed in Pubmed: 22035768.
• 22. Indolfi C, Di Lorenzo E, Perrino C, et al. Hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin prevents cardiac hypertrophy induced by pressure overload and inhibits p21ras activation. Circulation. 2002; 106(16): 2118–2124, doi: 10.1161/01.cir.0000034047.70205.97, indexed in Pubmed: 12379583.
• 23. Jaeschke H. Mechanisms of oxidant stress-induced acute tissue injury. Proc Soc Exp Biol Med. 1995; 209(2): 104–111, doi: 10.3181/00379727-209-43885b, indexed in Pubmed: 7770460.
• 24. Jalil JE, Doering CW, Janicki JS, et al. Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle. Circ Res. 1989; 64(6): 1041–1050, doi: 10.1161/01.res.64.6.1041, indexed in Pubmed: 2524288.
• 25. Kaden J. IL-6 determination in serum of kidney graft recipients by a new bedside test: its diagnostic relevance. Transplant Proc. 2007; 39(2): 511–513, doi: 10.1016/j.transproceed.2006.12.015, indexed in Pubmed: 17362770.
• 26. Kapur NK, Musunuru K. Clinical efficacy and safety of statins in managing cardiovascular risk. Vasc Health Risk Manag. 2008; 4(2): 341–353, doi:10.2147/vhrm.s1653, indexed in Pubmed: 18561510.
• 27. Kelly RA, Balligand JL, Smith TW. Nitric oxide and cardiac function. Circ. Res. 1996; 79(3): 363–380, doi: 10.1161/01.res.79.3.363, indexed in Pubmed:8781470.
• 28. Leenen FH. Cardiovascular consequences of sympathetic hyperactivity. Can J Cardiol. 1999; 15 Suppl A: 2A–7A, indexed in Pubmed: 10205250.
• 29. Lefer DJ, Granger DN. Oxidative stress and cardiac disease. Am J Med. 2000; 109(4): 315–323, doi: 10.1016/s0002-9343(00)00467-8, indexed in Pubmed: 10996583.
• 30. Lin Y, Wang LN, Xi YH, et al. L-arginine inhibits isoproterenol-induced cardiac hypertrophy through nitric oxide and polyamine pathways. Basic Clin Pharmacol Toxicol. 2008; 103(2): 124–130, doi: 10.1111/j.1742-7843.2008.00261.x, indexed in Pubmed: 18816294.
• 31. Liu YH, Carretero OA, Cingolani OH, et al. Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction. Am J Physiol Heart Circ Physiol. 2005; 289(6): H2616–H2623, doi: 10.1152/ajpheart.00546.2005, indexed in Pubmed: 16055518.
• 32. Lloyd-Jones DM, Larson MG, Leip EP, et al. Framingham Heart Study. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation. 2002; 106(24): 3068–3072, doi: 10.1161/01.cir.0000039105.49749.6f, indexed in Pubmed: 12473553.
• 33. Martín-Fernández B, de las Heras N, Miana M, et al. Spironolactone prevents alterations associated with cardiac hypertrophy produced by isoproterenol in rats: involvement of serum- and glucocorticoid-regulated kinase type 1. Exp Physiol. 2012; 97(6): 710–718, doi:10.1113/expphysiol.2011.063230, indexed in Pubmed: 22327331.
• 34. Masson S, Arosio B, Luvarà G, et al. Remodelling of cardiac extracellular matrix during beta-adrenergic stimulation: upregulation of SPARC in the myocardium of adult rats. J Mol Cell Cardiol. 1998; 30(8): 1505–1514, doi: 10.1006/jmcc.1998.0714, indexed in Pubmed: 9737937.
• 35. McKinsey TA, Kass DA. Small-molecule therapies for cardiac hypertrophy: moving beneath the cell surface. Nat Rev Drug Discov. 2007; 6(8): 617–635, doi: 10.1038/nrd2193, indexed in Pubmed: 17643091.
• 36. Mungrue IN, Gros R, You X, et al. Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. J Clin Invest. 2002; 109(6): 735–743, doi: 10.1172/JCI13265, indexed in Pubmed: 11901182.
• 37. Murray DR, Prabhu SD, Chandrasekar B. Chronic beta-adrenergic stimulation induces myocardial proinflammatory cytokine expression. Circulation. 2000; 101(20): 2338–2341, doi: 10.1161/01.cir.101.20.2338, indexed in Pubmed: 10821806.
• 38. Nadruz W, Lagosta VJ, Moreno H, et al. Simvastatin prevents load-induced protein tyrosine nitration in overloaded hearts. Hypertension. 2004; 43(5): 1060–1066, doi: 10.1161/01.HYP.0000124252.43470.2c, indexed in Pubmed: 15023931.
• 39. Narang D, Sood S, Thomas M, et al. Dietary palm olein oil augments cardiac antioxidant enzymes and protects against isoproterenol-induced myocardial necrosis in rats. J Pharm Pharmacol. 2005; 57(11): 1445–1451, doi: 10.1211/jpp.57.11.0010, indexed in Pubmed: 16259777.
• 40. Porter KE, Turner NA. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther. 2009; 123(2): 255–278, doi:10.1016/j.pharmthera.2009.05.002, indexed in Pubmed: 19460403.
• 41. Querejeta R, López B, González A, et al. Increased collagen type I synthesis in patients with heart failure of hypertensive origin: relation to myocardial fibrosis. Circulation. 2004; 110(10): 1263–1268, doi: 10.1161/01.CIR.0000140973.60992.9A, indexed in Pubmed: 15313958.
• 42. RONA G, CHAPPEL CI, BALAZS T, et al. An infarct-like myocardial lesion and other toxic manifestations produced by isoproterenol in the rat. AMA Arch Pathol. 1959; 67(4): 443–455, indexed in Pubmed: 13636626.
• 43. Rona G. Catecholamine cardiotoxicity. J Mol Cell Cardiol. 1985; 17(4): 291–306, doi: 10.1016/s0022-2828(85)80130-9, indexed in Pubmed: 3894676.
• 44. Shah AM, MacCarthy PA. Paracrine and autocrine effects of nitric oxide on myocardial function. Pharmacol Ther. 2000; 86(1): 49–86, doi:10.1016/s0163-7258(99)00072-8, indexed in Pubmed: 10760546.
• 45. Shizukuda Y, Buttrick PM, Geenen DL, et al. beta-adrenergic stimulation causes cardiocyte apoptosis: influence of tachycardia and hypertrophy. Am J Physiol. 1998; 275(3 Pt 2): H961–H968, indexed in Pubmed: 9724301.
• 46. Siwik DA, Pagano PJ, Colucci WS. Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol. 2001; 280(1): C53–C60, indexed in Pubmed: 11121376.
• 47. Song W, Lu X, Feng Q. Tumor necrosis factor-alpha induces apoptosis via inducible nitric oxide synthase in neonatal mouse cardiomyocytes. Cardiovasc Res. 2000; 45(3): 595–602, doi: 10.1016/s0008-6363(99)00395-8, indexed in Pubmed: 10728381.
• 48. Stevens A, Wilson I. The haematoxylins and eosin. In: Bancroft J, editors. Theory and Practice of Histological Techqniues. 4th ed. Churchill Livingstone, London, New York, Toronto. 1999: pp. 99–112.
• 49. Sun Y, Carretero OA, Xu J, et al. Lack of inducible NO synthase reduces oxidative stress and enhances cardiac response to isoproterenol in mice with deoxycorticosterone acetate-salt hypertension. Hypertension. 2005; 46(6): 1355–1361, doi: 10.1161/01.HYP.0000192651.06674.3f, indexed in Pubmed: 16286571.
• 50. Swan HJ. Left ventricular dysfunction in ischemic heart disease: fundamental importance of the fibrous matrix. Cardiovasc Drugs Ther. 1994; 8 Suppl 2: 305–312, doi: 10.1007/bf00877314, indexed in Pubmed: 7947372.
• 51. Takemoto M, Node K, Nakagami H, et al. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest. 2001; 108(10): 1429–1437, doi: 10.1172/JCI13350, indexed in Pubmed: 11714734.
• 52. Taylor PB, Tang Q. Development of isoproterenol-induced cardiac hypertrophy. Can J Physiol Pharmacol. 1984; 62(4): 384–389, doi: 10.1139/y84-191, indexed in Pubmed: 6203632.
• 53. Teerlink JR, Pfeffer JM, Pfeffer MA. Progressive ventricular remodeling in response to diffuse isoproterenol-induced myocardial necrosis in rats. Circ Res. 1994; 75(1): 105–113, doi: 10.1161/01.res.75.1.105, indexed in Pubmed: 8013068.
• 54. Torres SH, De Sanctis JB, de L Briceño M, et al. Inflammation and nitric oxide production in skeletal muscle of type 2 diabetic patients. J Endocrinol. 2004; 181(3): 419–427, doi: 10.1677/joe.0.1810419, indexed in Pubmed: 15171690.
• 55. Touyz RM. Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what is the clinical significance? Hypertension. 2004; 44(3): 248–252, doi: 10.1161/01.HYP.0000138070.47616.9d, indexed in Pubmed: 15262903.
• 56. Vasan RS, Levy D. The role of hypertension in the pathogenesis of heart failure. A clinical mechanistic overview. Arch Intern Med. 1996; 156(16): 1789–1796, doi: 10.1001/archinte.156.16.1789, indexed in Pubmed: 8790072.
• 57. Wan LH, Chen J, Li L, et al. Protective effects of Carthamus tinctorius injection on isoprenaline-induced myocardial injury in rats. Pharm Biol. 2011; 49(11): 1204–1209, doi: 10.3109/13880209.2011.576348, indexed in Pubmed: 22014268.
• 58. Warren CM, Jordan MC, Roos KP, et al. Titin isoform expression in normal and hypertensive myocardium. Cardiovasc Res. 2003; 59(1): 86–94, doi:10.1016/s0008-6363(03)00328-6, indexed in Pubmed: 12829179.
• 59. Xia Y, Zweier JL. Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages. Proc Natl Acad Sci USA. 1997; 94(13): 6954–6958, doi: 10.1073/pnas.94.13.6954, indexed in Pubmed: 9192673.
• 60. Yang J, Wang HX, Zhang YJ, et al. Astragaloside IV attenuates inflammatory cytokines by inhibiting TLR4/NF-kB signaling pathway in isoproterenol-induced myocardial hypertrophy. J Ethnopharmacol. 2013 [Epub ahead of print], doi: 10.1016/j.jep.2013.10.017, indexed in Pubmed: 24513635.
• 61. Zhang P, Xu X, Hu X, et al. Inducible nitric oxide synthase deficiency protects the heart from systolic overload-induced ventricular hypertrophy and congestive heart failure. Circ Res. 2007; 100(7): 1089–1098, doi: 10.1161/01.RES.0000264081.78659.45, indexed in Pubmed: 17363700.

Identyfikatory

DOI

10.5603/FM.a2016.004