Effect of chronic AT(1) receptor blockade on cardiac Smad overexpression in hereditary cardiomyopathic hamsters

Objective: As the pharmacological suppression of angiotensin has been assoc iated with cardioprotective effects in cardiomyopathy, our primary aim was to determine whether the expression of Smad protein components of the cardi ac TGF-beta signaling cascade is modulated by chronic AT, receptor blockade . Furthermore, we examined the relationship between cardiac Smad protein ex pression and altered collagen turnover in the cardiomyopathic heart. Method s: Male UM-X7.1 cardiomyopathic (CMP) Syrian hamsters at early (65 days) an d late (200 days) stages of cardiomyopathy were subjected to 4 week losarta n (15 mg/kg/day) treatment. Expression of left ventricular (LV receptor-act ivated (Smad 2) and common-mediator (Smad 4) Smads from control (F1-beta st rain) hamsters, non-treated cardiomyopathic (CMP), and losartan-treated CMP animals was assessed. Collagen turnover, including fibrillar collagen synt hesis/accretion and cardiac MMP activity was assessed. Results: Elevated mR NA abundance of fibrillar collagens and ANF were present in cardiomyopathic hearts and these trends were normalized in the early stage losartan-treate d group. 4-Hydroxyproline and zymographic assays confirmed fibrosis and ele vated MMP-1 and -2 activities in CMP hearts. Losartan treatment was associa ted with a modest reduction of cardiac 4-hydroxyproline concentration, and a significant reduction of both MMP-1 and MMP-2 activities. While TGF-beta( 1) mRNAs were elevated in both CMP groups vs. controls, total TGF-beta prot ein content was not different in CMP vs. controls. In LV preparations conta ining nuclear extract, elevated Smad 2 and Smad 4 protein expression was no ted in cardiomyopathic hearts vs, controls. Losartan treatment of late-stag e CMP hamsters was associated with a significant reduction in Smad ? and a modest reduction of Smad 4 protein expression vs. untreated CMP samples. Co nclusions: Altered cardiac Smad expression, present in both early and late stage cardiomyopathy, is positively correlated with the occurrence of cardi ac fibrosis and elevated collagen turnover in failing CMP hearts. Four week AT(1) blockade is associated with normalized expression of cardiac Smad 2 proteins, and these changes occur in parallel with some aspects of collagen turnover in failing cardiomyopathic hearts. (C) 2000 Elsevier Science B.V. All rights reserved.