EFFECT OF AT(1) RECEPTOR BLOCKADE ON CARDIAC COLLAGEN REMODELING AFTER MYOCARDIAL-INFARCTION

Objective: Previous work has shown that cardiac fibrosis occurs after myocardial infarction (MI) in non-infarcted ventricular tissue and tha t this event is associated with abnormal cardiac function. Our aim was to investigate the effect of AT, receptor blockade on cardiac collage n remodeling in post-MI rat heart remote from the infarct site by addr essing collagen mRNA abundance, posttranslational hydroxylation of col lagen monomers, and mature collagen deposition. Prolyl 4-hydroxylase ( PH) mediates hydroxylation of procollagen a-chains in the endoplasmic reticulum of cardiac fibroblasts and thus regulates the downstream for mation and secretion of helical procollagen molecules, Methods: The ef fects of losartan (15 mg/kg/day) on collagen deposition and mRNA abund ance were monitored in viable left and right ventricles in sham-operat ed (control) and experimental groups in the presence or absence of los artan. Immunoreactive PH concentration in viable tissues as well as ca rdiac function in control and experimental groups was determined by EL ISA. Results: Immunohistochemical staining and 4-hydroxyproline assays confirmed that losartan treatment attenuates fibrosis in experimental hearts. Northern analysis revealed that losartan treatment of 1, 2, o r 4 week experimental groups had no effect on collagen mRNA abundance compared to untreated post-MI rats. On the other hand, immunoreactive PH concentration was significantly decreased in the post-MI group trea ted with losartan, Determination of cardiac mass and cardiac function revealed that losartan treatment was associated with attenuated cardia c hypertrophy and improved left ventricular (LV) function in experimen tal animals. Conclusions: AT(1) blockade is associated with a signific ant decrease in cardiac fibrosis in treated post-MI rats, and this tre nd is positively correlated to a significant decrease in immunoreactiv e PH compared to untreated experimental animals. The expression of car diac PH may be regulated by angiotensin via AT(1) receptor activation, and the suppression of PH with losartan treatment may be an important mechanism for modulation of collagen deposition in the post-MI rat he art. (C) 1997 Elsevier Science B.V.