EFFECT OF RENNIN INHIBITORS AND ANGIOTENSIN II RECEPTOR ANTAGONISTS ON LEFT VENTRICULAR HYPERTROPHY IN RENOVASCULAR HYPERTENSIVE RATS
Objective: Left ventricular (LV) hypertrophy involves numerous structural adaptations that may lead to ventricular dysfunction and eventually, heart failure. Particular emphasis is placed on the molecular mechanisms that govern the development of hypertrophy and may lead to maladaptive structural changes resulting in adverse cardiac events. This study investigates the effectiveness of Valsartan (Val) which is an angiotensinII receptor antagonist and Aliskiren (Ali) which is a direct rennin inhibitor in the treatment of cardiac remodeling resulted from renovascular hypertension, particularly left ventricular hypertrophy, and to address the molecular mechanisms underlying them.
Methods: 24 male albino rats were randomly divided into 4 main groups (n=6 each), normal control rats (N), hypertensive control rats (HC), Val treated hypertensive rats (Val, 8 mg/kg/day orally) and Ali treated hypertensive rats (Ali, 25 mg/kg/day orally).
Results: At the end of 4 weeks HC rats showed enhanced hypertrophic response (higher heart weight/body weight ratio) and dyslipidemia (lower high density lipoprotein "HDL-c" and higher triacyl glycerol "TAG") and a significant deletion of antioxidant enzymes in comparison with N group. The Î² myosin heavy chain "Î²MHC", regulator of calcineurin-1 "RCAN1", nuclear factor kappa B "NFÎºB" and inducible nitric oxide synthase "iNOS" was markedly elevated. While, Î± myosin heavy chain "Î±MHC" was markedly decreased as compared with N group. On the other hand Val treated hypertensive rats and Ali treated hypertensive rats showed a significant decrease in heart weight/body weight ratio, improved lipogram pattern and higher levels of antioxidant enzymes. While, cardiac Î²-MHC, RCAN-1, NFÎºB and iNOS were significantly decreased as compared with HC group. Both Val treated hypertensive rats and Ali treated hypertensive rats showed a significant increase in Î±-MHC, compared with HC group
Conclusion: The results reported in this study suggested that chronic untreated hypertension induced a pathological hypertrophy. Administration of the Val or Ali individually exerted beneficial effects regarding the improved lipogram pattern and anti-oxidant enzymes levels, as well as cardiac hypertrophy and highlights the role of Val and Ali as a promising therapeutic strategy for hypertension and LV hypertrophy.
2. Bella JN, GÃ¶ring HH. Genetic epidemiology of left ventricular hypertrophy. Am J Cardiovasc Dis 2012;2:267-78.
3. Iravanian S, Dudley SC. The renin-angiotensin-aldosterone system (RAAS) and cardiac arrhythmias. Heart Rhythm 2008;5:s12â€“s7.
4. Schmieder RE, Hilgers KF, Schlaich MP, Schmidt BM. Renin-angiotensin system and cardiovascular risk. Lancet 2007;369:1208-19.
5. Hong HJ, Chan P, Liu JC, Juan SH, Huang MT, Lin JG, et al. Angiotensin II induces endothelin-1 gene expression via extracellular signal-regulated kinase pathway in rat aortic smooth muscle cells. Cardiovasc Res 2004;61:159-68.
6. Rashid HU. Renoprotection, renin inhibition, and blood pressure control: the impact of aliskiren on integrated blood pressure control. Integr Blood Pressure Control 2010;3:133â€“44.
7. Whaley-Connell A, Johnson MS, Sowers JR. Aldosterone: role in the cardiometabolic syndrome and resistant hypertension. Prog Cardiovasc Dis 2010;52:401â€“9.
8. Ni J, Ma KL, Wang CX, Liu J, Zhang Y, Lin-LL, et al. Activation of renin-angiotensin system is involved in dyslipidemia-mediated renal injuries in apolipoprotein E knockout mice and HK-2 cells. Lipids Health Dis 2013;9:12-49.
9. Fanelli C, Zatz R. Linking oxidative stress, the renin-angiotensin system and hypertension. Hypertens 2011;57:373-4.
10. Verdecchia P, Angeli F, Mazzotta G, Gentile G, Reboldi G. The renin angiotensin system in the development of cardiovascular disease: role of aliskiren in risk reduction. Vasc Health Risk Manage 2008;4:971-81.
11. Gerald WD, Jeffrey R, Peter HS. Phenotyping hypertrophy. Circ Res 2003;92:1171-5.
12. Pandya K, Smithies O. Î²-MHC and cardiac hypertrophy. Circ Res 2011;109:609-10.
13. Wilkins BJ, Molkentin JD. Calciumâ€“calcineurin signaling in the regulation of cardiac hypertrophy. Biochem Biophys Res Commun 2004;322:1178â€“91.
14. Shin SY, Yang HW, Kim JR, Heo WD, Cho KH. A hidden incoherent switch regulates RCAN1 in the calcineurinâ€“NFAT signaling network. J Cell Sci 2011;124:82-90.
15. Vega RB, Rothermel BA, Weinheimer CJ, Kovacs A, Naseem RH, Bassel-Duby R, et al. Dual roles of modulatory calcineurin-interacting protein 1 in cardiac hypertrophy. Proc Nat Acad Sci USA 2003;100:669-74.
16. Saydam T. Bioavailability file: Valsartan. FABAD J Pharm Sci 2007;32:185-96.
17. Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet 2000;355:637-45.
18. Verdecchia P, Angeli F. Assessment of the optimal daily dose of valsartan in patients with hypertension, heart failure, or Both. Clin Ther 2004;26:460-72.
19. Stanton AV, Gradman AH, Schmieder RE, Nussberger J, Sarangapani R, Prescott MF. Aliskiren monotherapy does not cause paradoxical blood pressure rises. Hypertens 2010;55:54-60.
20. Gowraganahalli J, Pitchai B, Norman S. How well do aliskiren's purported mechanisms track its effects on cardiovascular and renal disorders? Cell Signalling 2012;24:1583â€“91.
21. Salguero G, Akin E, Templin C, Kotlarz D, Doerries C, Landmesser U, et al. Renovascular hypertension by two-kidney one-clip enhances endothelial progenitor cell mobilization in a p47phox-dependent manner. Hypertens 2008;26:257â€“68.
22. Yamamoto E, Kataoka K, Dong YF, Nakamura T, Fukuda M, Tokutomi Y, et al. Aliskiren enhances the protective effects of valsartan against cardiovascular and renal injury in endothelial nitric oxide synthase-deficient mice. Hypertens 2009;54:633-8.
23. Polizio AH, Balestrasse KB, Yannarelli GG, Noriega GO, Gorzalczany S, Taira C, et al. Angiotensin II regulates cardiac hypertrophy via oxidative stress but not antioxidant enzyme activities in experimental reno-vascular hypertension. Hypertens Res 2008;31:325-34.
24. Kiers HD, Hofstra JM, Wetzels JFM. Oscillometric blood pressure measurements: differences between measured and calculated mean arterial blood pressure. J Med 2008;66:474-9.
25. Burstein M, Scholnick HR, Morfin R. Rapid method for isolation of lipoproteins from human serum by precipitation with polyanions. J Lipid Res 1970;11:583-95.
26. Fassati P, prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem 1982;28:2077-80.
27. Chomczynski P, Sacchi N. The single-step method of RNA isolation by acid guanidinium thiocyanateâ€“phenolâ€“chloroform extraction: twenty-something years on. Nat Protoc 2006;1:581-5.
28. Dury RA, Wallington EA. Histological technique. 5th ed. Oxford, NY Toronto; 1987. p. 27-9.
29. Coons AH, Creech HJ, Jones RN. Immunological properties of an antibody containing a fluorescent group. Proc Soc Exp Biol Med 1941;47:200-2.
30. Ernsberger P, Koletsky RJ. Metabolic actions of angiotensin receptor antagonists: PPAR-Î³ agonist actions or a class effect? Curr Opin Pharmacol 2007;7:140-5.
31. Chu KY, Lau T, Carlsson PO, Leung PS. Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes. Diabetologica 2006;55:367â€“74.
32. Neeli H, Gadi R, Rader DJ. Managing diabetic dyslipidemia: beyond statin therapy. Curr Diabetes Rep 2009;9:11-7.
33. De Grooth GJ, Klerkx AH, Stroes ES, Stalenhoef AF, Kastelein JJ, Kuivenhoven JA. Areview of CETP and its relation to atherosclerosis. J Lipid Res 2004;45:1967-74.
34. Virdis A, Duranti D, Taddei S. Oxidative stress and vascular damage in hypertension: role of angiotensin II. J Int Hypertens 2011;2011:1-7.
35. Nickenig G, Strehlow K, BÃ¤umer AT, Baudler S, Wassmann S, Sauer H, et al. Negative feedback regulation of reactive oxygen species on AT1 receptor gene expression. Br J Pharmacol 2000;131:795-803.
36. Ahmad A, Singhal U, Hossain MM, Islam N, Rizvi I. The role of the endogenous antioxidant enzymes and malondialdehyde in essential hypertension. JCDR 2013;7:987-90.
37. Simic DV, Mimic-Oka J, Pljesa-Ercegovac M, Savic-Radojevic A, Opacic M, Matic D, et al. Byproducts of oxidative protein damage and antioxidant enzyme activities in plasma of patients with different degrees of essential hypertension. J Hum Hypertens 2006;20:149-55.
38. Hilfiker-Kleiner D, Hilfiker A, Schieffer B, Engel D, Mann DL, Wollert KC, et al. TNFÎ± decreases Î±MHC expression by a NO mediated pathway: role of E-box transcription factors for cardiomyocyte specific gene regulation. Cardiovasc Res 2002;53:460-9.
39. Krenz M, Robbins J. Impact of beta-myosin heavy chain expression on cardiac function during stress. J Am Coll Cardiol 2004;44:2390-7.
40. Benjamin JW, Jeffery DM. Calcineurin and cardiac hypertrophy: Where have we been? Where are we going? J Phys 2002;54:1-8.
41. Casas C, MartÃnez S, Pritchard MA, Fuentes JJ, Nadal M, GuimerÃ J, et al. Dscr1, a novel endogenous inhibitor of calcineurin signaling, is expressed in the primitive ventricle of the heart and during neurogenesis. Mech Dev 2001;101:289â€“92.
42. Yang J, Rothermel B, Vega RB, Frey N, McKinsey TA, Olson EN, et al. Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles. Circ Res 2000;87:e61â€“e8.
43. Leychenko A, Konorev E, Jijiwa M, Matter ML. Stretch-induced hypertrophy activates NFkB-mediated VEGF secretion in adult cardiomyocytes. PLoS One 2011;6:e29055.
44. SoskiÄ‡ SS, DobutoviÄ‡ BD, Sudar EM, ObradoviÄ‡ MM, NikoliÄ‡ DM, Djordjevic JD, et al. Regulation of inducible nitric oxide synthase (iNOS) and its potential role in insulin resistance, diabetes and heart failure. Open Cardiovasc Med J 2011;5:153â€“63.
45. Zentilin L, Puligadda U, Lionetti V, Zacchigna S, Collesi C, Pattarini L, et al. Cardiomyocyte VEGFR-1 activation by VEGF-B induces compensatory hypertrophy and preserves cardiac function after myocardial infarction. FASEB J 2010;24:1467â€“78.
46. Henderson BC, Sen U, Reynolds C, Moshal KS, Ovechkin A, Tyagi N, et al. Reversal of systemic hypertension-associated cardiac remodeling in chronic pressure overload myocardium by ciglitazon. Int J Biol Sci 2007;3:385-92.
47. Dias FA, Urboniene D, Yuzhakova MA, Biesiadecki BJ, Pena JR, Goldspink PH, et al. Ablation of iNOS delays cardiac contractile dysfunction in chronic hypertension. Front Biosci 2010;2:312-24.
48. Ziolo MT, Maier LS, Piacentino V, Bossuyt J, Houser SR, Bers DM. Myocyte nitric oxide synthase 2 contributes to blunted beta-adrenergic response in failing human hearts by decreasing Ca2+transients. Circ 2004;109:1886-91.
49. Heusch P, Aker S, Boengler K, Deindl E, Van de Sand A, Klein K, et al. Increased inducible nitric oxide synthase and arginase II expression in heart failure: no net nitrite/nitrate production and protein S-nitrosylation. Am J Physiol Heart Circ Physiol 2010;299:H446-53.
50. Moinuddin G, Inamdar MN, Kulkarni KS, Kulkarni C. Modulation of hemodynamics, endogenous antioxidant enzymes, and pathophysiological changes by angiotensin-converting enzyme inhibitors in pressure-overload rats. J Cardiol 2011;52:216-26.
51. Munger MA. Use of angiotensin receptor blockers in cardiovascular protection: current evidence and future direction. P T 2011;36:22-40.
52. Marshall TG, Lee RE, Marshall FE. Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b. Theor Biol Med Modell 2006;10:1.
53. Nishida Y, Takahashi Y, Nakayama T, Asai S. Comparative effect of angiotensin II type I receptor blockers and calcium channel blockers on laboratory parameters in hypertensive patients with type 2 diabetes. Cardiovasc Diabetol 2012;11:53.
54. Goyal S, Bharti S, Sahoo KC, Sharma AK, Arya DS. Valsartan, an angiotensin II receptor blocker attenuates cardiac dysfunction and oxidative stress in isoproterenol-induced cardiotoxicity. Cardiovasc Toxicol 2011;11:148-56.
55. Cohn JN, Tognoni G. Valsartan heart failure trial investigators. Val HEFT trial; randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667â€“75.
56. Delcayre C, Silvestre JS, Garnier A, Oubenaissa A, Cailmail S, Tatara E, et al. Cardiac aldosterone production and ventricular remodeling. Kidney Int 2000;57:1346â€“51.
57. Wang B, Ouyang J, Xia Z. Effects of triiodo-thyronine on angiotensin-induced cardiomyocyte hypertrophy: reversal of increased Î²-myosin heavy chain gene expression. Can J Physiol Pharmacol 2006;84:935-41.
58. Esteban V, MÃ©ndez-Barbero N, JimÃ©nez-Borreguero LJ, RoquÃ© M, NovensÃ¡ L, GarcÃa-Redondo AB, et al. Regulator of calcineurin 1 mediates pathological vascular wall remodeling. J Exp Med 2011;208:2125-39.
59. Johar S, Cave AC, Narayanapanicker A, Grieve DJ, Shah AM. Aldosterone mediates angiotensin II-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase. FASEB J 2006;20:1546-8.
60. Griendling KK, Ushio-Fukai M. Reactive oxygen species as mediators of angiotensin II signaling. Regul Pept 2000;91:21â€“7.
61. Yamakawa H, Jezova M, Ando H, Saavedra JM. Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition. J Cereb Blood Flow Metab 2003;23:371â€“80.
62. RodrÃguez-Penas D, FeijÃ³o-BandÃn S, Lear PV, Mosquera-Leal A, GarcÃa-RÃºa V, Otero MF, et al. Aliskiren affects fatty-acid uptake and lipid-related genes in rodent and human cardiomyocytes. Biocatal Pharm 2011;82:491-504.
63. Kalupahana NS, Massiera F, Quignard-Boulange A, Ailhaud G, Voy BH, Wasserman DH, et al. Overproduction of angiotensinogen from adipose tissue induces adipose inflammation, glucose intolerance and insulin resistance. Obesity (Silver Spring) 2012;20:48â€“56.
64. Yvan-Charvet L, Bobard A, Bossard P, MassiÃ©ra F, Rousset X, Ailhaud G, et al. In vivo evidence for a role of adipose tissue SR-BI in the nutritional and hormonal regulation of adiposity and cholesterol homeostasis. Arterioscler Thromb Vasc Biol 2007;27:1340â€“5.
65. Ozeki A, Amiya E, Watanabe M, Hosoya Y, Takata M, Watanabe A, et al. Effect of add-on aliskiren to type 1 angiotensin receptor blocker therapy on endothelial function and autonomic nervous system in hypertensive patients with ischemic heart disease. J Clin Hypertens 2014;16:591-8.
66. Cruzado MC, Risler NR, Miatello RM, Yao G, Schiffrin EL, Touyz RM. Vascular smooth muscle cell NAD(P)H oxidase activity during the development of hypertension: effect of Ang II and role of insulin like growth factor-1 receptor transactivation. Am J Hypertens 2005;18:81-7.
67. Kim S, Yoshiyama M, Izumi Y, Kawano H, Kimoto M, Zhan Y, et al. Effects of combination of ACE inhibitor and angiotensin receptor blocker on cardiac remodeling, cardiac function, and survival in rat heart failure. Circ 2001;103:148-54.
68. Sakoda M, Ichihara A, Kurauchi-Mito A, Narita T, Kinouchi K, Murohashi-Bokuda K, et al. Aliskiren inhibits intracellular angiotensin II levels without affecting (pro)renin receptor signals in human podocytes. Am J Hypertens 2010;23:575-80.
69. SÃ¡nchez-Lemus E, Benicky J, Pavel J, Larrayoz IM, Zhou J, Baliova M, et al. Angiotensin II AT1 blockade reduces the lipopolysaccharide-induced innate immune response in rat spleen. Am J Physiol Regulatory Integrative Comparative Physiol 2009;296:R1376â€“R84.
70. Cole BK, Keller SR, Wu R, Carter JD, Nadler JL, Nunemaker CS. Valsartan protects pancreatic islets and adipose tissue from the inflammatory and metabolic consequences of high-fat diet in mice. Hypertens 2010;55:715â€“21.
71. Higashikuni Y, Takaoka M, Iwata H, Tanaka K, Hirata Y, Nagai R, et al. Aliskiren in combination with valsartan exerts synergistic protective effects against ventricular remodeling after myocardial infarction in mice. Hypertens Res 2012;35:62â€“9.
72. De Gasparo M, Hess P, Clozel M, Persohn E, Roman D, Germann PG, et al. Combination of low-dose valsartan and enalapril improves endothelial dysfunction and coronary reserve in N[omega]-nitro-l-arginine methyl ester-treated spontaneously hypertensive rats. J Card Pharm 2002;40:789-800.