Connective tissue growth factor induction in a pressure-overloaded heart ameliorated by the angiotensin II type 1 receptor blocker olmesartan

Abstract

Connective tissue growth factor (CTGF) is a secreted protein that regulates fibrosis. We hypothesized that CTGF is induced in a pressure-overloaded (PO) heart and that blocking the angiotensin II type 1 receptor would reduce CTGF expression. Accordingly, we administered olmesartan and compared its effects with other antihypertensive drugs in a PO heart. CTGF induction was determined in a rat PO model, and olmesartan, hydralazine or saline was continuously administered. The effects of olmesartan on CTGF induction, myocyte hypertrophy and fibrosis were evaluated. The effect of olmesartan on cardiac function was also examined in CTGF-and transforming growth factor-beta 1 (TGF-b1)-infused rats. CTGF was increased in the PO heart 3 days after aortic banding and was markedly distributed around the perivascular fibrotic area. After 28 days, blood pressure was not significantly different in the olmesartan and hydralazine groups, but olmesartan treatment reduced CTGF distribution in PO hearts. Olmesartan was associated with a significantly reduced myocyte hypertrophy index (4.77 ± 0.48 for olmesartan and 6.05 ± 1.45 for saline, Po0.01), fibrosis area (32.0 ± 15.5% compared with the saline group, Po0.05) and serum TGF-b1 level (62.6±10.6 ng ml À1 for olmesartan and 84.4±7.2 ng ml À1 for hydralazine, Po0.05). In addition, cardiac function was significantly preserved in the olmesartan group compared with the saline group. Finally, olmesartan ameliorated the cardiac dysfunction in CTGF-and TGF-b1-infused rats. Olmesartan attenuated CTGF induction, reduced perivascular fibrosis and ameliorated cardiac dysfunction in a PO heart. Our results provide insight into the beneficial effects of olmesartan on PO hearts, independent of blood-pressure lowering.

Expression profile of matricellular proteins in hypertrophied right ventricle of monocrotaline-induced pulmonary hypertensive rats

“…3). In the CCN family, CCN2 (connective tissue growth factor, CTGF) is supposed to promote hypertrophic reactions and fibrosis in pressure-overloaded heart, although its effect is indirect [12]. In contrast, it is suggested that CCN5 inhibits cardiac hypertrophy and fibrosis through effects on CCN2 [33].…”

Atrial expression of the CCN1 and CCN2 proteins in chronic heart failure

“…The addition of angiotensin II to fibroblast culture elevated CCN2 mRNA and protein [19]. Pressure overload of the left ventricle of the heart caused increased expression of CCN2 protein, that was abolished by olmesartan -another AT1 receptor antagonist [20]. Although this protein may be responsible for increased deposition of connective tissue also in the atrial myocardium, there has been no direct investigation targeting this specific issue to date.…”

Matricellular Proteins in Cardiac Adaptation and Disease

“…Marked and consistent CCN2 induction is found in cardiac hypertrophy due to pressure overload, or angiotensin II infusion (205), (134), in models of diabetic cardiomyopathy (476), in a porcine model of pacing-induced cardiomyopathy (10), in aging-associated murine cardiac fibrosis (473), in the mdx mouse model of dystrophic cardiomyopathy (22) and in a model of cardiac fibrosis due to viral myocarditis (247). Much like in the infarcted heart, TGF-β, angiotensin II and endothelin-1 may be involved in mediating CCN2 upregulation in the hypertrophied ventricle.…”