Abstract
Aim:
To study whether urotensin II (UII), a potent vasoconstrictive peptide, is involved in the development of cardiac hypertrophy and fibrogenesis of rats induced by isoproterenol (ISO).
Methods:
Thirty male Wistar rats were randomly divided into 3 groups. Group 1 was the healthy control group, group 2 was the ISO group, and group 3 was the ISO+UII group. In groups 2 and 3, ISO (5 mg·kg−1·d−1) was given (sc) once daily for 7 d. Group 3 was also given UII in the first day [3 nmol/kg (5 ug/kg), iv], followed by sc (1.5 ug/kg) twice daily. Group 1 received 0.9% saline. UII receptor (UT) mRNA expression was determined by RT-PCR. The contents of UII and angiotensin II (Ang II) were determined by radioimmunoassay. In vitro, the effects of UII on DNA/collagen synthesis of cardiac fibroblasts were determined by [3H]thymidine/[3H]proline incorporation.
Results:
The ratio of heart weight/body weight, plasma lactate dehydrogenase activity, myocardial malondialdehyde and hydroxyproline concentration increased significantly in the ISO group, as well as UT mRNA expression, plasma and cardiac UII and ventricular Ang II, compared with the control group (P<0.01). ISO induced significant myocardial fibrogenesis. Moreover, UII+ISO co-treatment significantly increased the changes of biochemical markers of injury and the degree of cardiac hypertrophy and fibrosis. In vitro, 5×10−9-5×10−7mol/L UII stimulated [3H]thymidine/[3H] proline incorporation into cardiac fibroblasts in a dose-dependent manner (P<0.01).
Conclusion:
These results suggest that UII was involved in the development of cardiac fibrosis and hypertrophy by synergistic effects with ISO.
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Coulouarn Y, Lihrmann I, Jegou S, Anouar Y, Tostivint H, Beauvillain JC, et al. Cloning of the cDNA encoding the urotensin II precursor in frog and human reveals intense expression of the urotensin II gene in motoneurons of the spinal cord. Proc Natl Acad Sci USA 1998; 95: 15803–8.
Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, et al. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 1999; 401: 282–6.
Douglas SA, Tayara L, Ohlstein EH, Halawa N, Giaid A . Congestive heart failure and expression of myocardial urotensin II. Lancet 2002; 359: 1990–7.
Johns DG, Ao Z, Naselsky D, Herold CL, Maniscalco K, Sarov-Blat L, et al. Urotensin-II-mediated cardiomyocyte hypertrophy: effect of receptor antagonism and role of inflammatory mediators. Naunyn Schmiedebergs Arch Pharmacol 2004; 370: 238–50.
Egginger JG, Camus A, Calas A . Urotensin-II expression in the mouse spinal cord. J Chem Neuroanat 2006; 31: 146–54.
Zhang YG, Qi YF, Xia CF, Pang YZ, Yang J, Zhang ZK, et al. Stimulating proliferation of aorta smooth muscle cells of rat by urotensin II. Chin Pharmacol Bull 2001; 17: 155–7.
Shi L, Ding W, Li D, Wang Z, Jiang H, Zhang J, et al. Proliferation and anti-apoptotic effects of human urotensin II on human endothelial cells. Atherosclerosis 2006; 188: 260–4.
Watanabe T, Suguro T, Kanome T, Sakamoto Y, Kodate S, Hagiwara T, et al. Human urotensin II accelerates foam cell formation in human monocyte-derived macrophages. Hypertension 2005; 46: 738–44.
Russell FD, Molenaar P . Investigation of signaling pathways that mediate the inotropic effect of urotensin-II in human heart. Cardiovasc Res 2004; 63: 673–81.
Gruson D, Rousseau MF, Ahn SA, van Linden F, Ketelslegers JM . Circulating urotensin II levels in moderate to severe congestive heart failure: Its relations with myocardial function and well established neurohormonal markers. Peptides 2006; 27: 1527–31.
Heringlake M, Kox T, Uzun O, Will B, Bahlmann L, Klaus S, et al. The relationship between urotensin II plasma immunore-activity and left ventricular filling pressures in coronary artery disease. Regul Pept 2004; 121: 129–36.
Russell FD, Meyers D, Galbraith AJ, Bett N, Toth I, Kearns P, et al. Elevated plasma levels of human urotensin-II immunoreactivity in congestive heart failure. Am J Physiol Heart Circ Physiol 2003; 285: H1576–81.
Zhang YG, Li JX, Cao J, Chen JJ, Yang J, Zhang ZK, et al. Effect of chronic hypoxia on contents of urotensin II and its functional receptors in rat myocardium. Heart Vessels 2002; 16: 64–8.
Tzanidis A, Hannan RD, Thomas WG, Onan D, Autelitano DJ, See F, et al. Direct actions of urotensin II on the heart: implications for cardiac fibrosis and hypertrophy. Circ Res 2003; 93: 246–53.
Watanabe T, Suguro T, Kanome T, Sakamoto Y, Kodate S, Hagiwara T, et al. Human urotensin II accelerates foam cell formation in human monocyte-derived macrophages. Hypertension 2005; 46: 738–44.
Watanabe T, Pakala R, Katagiri T, Benedict CR . Synergistic effect of urotensin II with mildly oxidized LDL on DNA synthesis in vascular smooth muscle cells. Circulation 2001; 104: 16–8.
Gallego M, Espina L, Vegas L, Echevarria E, Iriarte MM, Casis O . Spironolactone and captopril attenuates isoproterenol-induced cardiac remodelling in rats. Pharmacol Res 2001; 44: 311–5.
Asakawa T, Matsushita S . Thiobarbituric acid test for detecting lipid peroxides. Lipids 1979; 14: 401–6.
Jiang W, Jiang HF, Cai DY, Pan CS, Qi YF, Pang YZ, et al. Relationship between contents of adrenomedullin and distributions of neutral endopeptidase in blood and tissues of rats in septic shock. Regul Pept 2004; 118: 199–208.
Stegemann H, Stalder K . Determination of hydroxyproline. Clin Chim Acta 1967; 18: 267–73.
Gurantz D, Cowling RT, Villarreal FJ, Greenberg BH . Tumor necrosis factor-alpha upregulates angiotensin II type 1 receptors on cardiac fibroblasts. Circ Res 1999; 85: 272–9.
Toraason M, Luken ME, Breitenstein M, Krueger JA, Biagini RE . Comparative toxicity of allylamine and acrolein in cultured myocytes and fibroblasts from neonatal rat heart. Toxicology 1989; 56: 107–17.
Yu SM, Tsai SY, Guh JH, Ko FN, Teng CM, Ou JT . Mechanism of catecholamine-induced proliferation of vascular smooth muscle cells. Circulation 1996, 94: 547–54.
Li YR . Biochemistry of extracellular mesenchyma and study methods, 1st ed. Beijing: People's Medical Publishing House; 1988.
Simpson CM, Penny DJ, Stocker CF, Shekerdemian LS . Urotensin-II is elevated in children with congenital heart disease. Heart 2006; 92: 983–4.
Birker-Robaczewska M, Boukhadra C, Studer R, Mueller C, Binkert C, Nayler O . The expression of urotensin II receptor (U2R) is up-regulated by interferon-gamma. J Recept Signal Transduct Res 2003; 23: 289–305.
Grimm D, Elsner D, Schunkert H, Pfeifer M, Griese D, Bruckschlegel G, et al. Development of heart failure following isoproterenol administration in the rat: role of the renin-angiotensin system. Cardiovasc Res 1998, 37: 91–100.
Gupta OP, Hanke W . Regulation of interrenal secretion in the axolotl, Ambystoma mexicanum. Exp Clin Endocrinol 1994; 102: 299–306.
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Project supported by the China Postdoctoral Science Foundation (No 2003033439) and supported by the National Natural Science Foundation of China (No 30470730) and the Medical Science Foundation of Hebei Province Health Department (No 2 K010).
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Zhang, Yg., Li, Yg., Liu, Bg. et al. Urotensin II accelerates cardiac fibrosis and hypertrophy of rats induced by isoproterenol. Acta Pharmacol Sin 28, 36–43 (2007). https://doi.org/10.1111/j.1745-7254.2007.00485.x
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DOI: https://doi.org/10.1111/j.1745-7254.2007.00485.x
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