ANGIOTENSIN-II, TRANSFORMING GROWTH FACTOR-BETA(1) AND REPAIR IN THE INFARCTED HEART

Tissue repair following myocardial infarction (MI) eventuates in fibro us tissue formation at the site of myocyte necrosis. Following a large transmural MT, fibrosis appears remote to the infarct site. This is a ssociated with extensive tissue remodeling that adversely affects vent ricular diastolic function. Substances involved in promoting fibrous t issue formation at MI and remote sites are under investigation. Angiot ensin II (AngII), generated at sites of repair, has been implicated. H owever, its regulatory role on fibrous tissue formation remains uncert ain. In the present study we sought to determine whether AngII is corr elated to transforming growth factor beta 1 (TGF-beta(1)) expression, a regulator of fibrous tissue formation, at these sites of tissue repa ir. Mie studied: (1) localization and expression of angiotensin conver ting enzyme (ACE), AngII receptors, TGF-beta(1) mRNA and its receptors in the infarcted rat heart: and (2) effect of AngII on TGF-beta(1) sy nthesis by chronic blockade of AT(1) receptors began at the time of su rgery by losartan in rats with MI. Hearts were studied at 4 weeks post -MI. We found: (1) low-density ACE, AngII and TGF-beta(1), receptor bi nding and low mRNA for type I collagen and TGF-B, in the normal heart; (2) fibrosis at sites of MI and remote to it, including endocardium a nd fibrosis of intraventricular septum, interstitial fibrosis of nonin farcted myocardium and fibrosis of visceral pericardium; (3) markedly increased (P<0.01) and colocalized ACE, AngII and TGF-beta(1) receptor binding, type I collagen and TGF-beta(1), mRNA at MI and remote sites of repair; (4) increased TGF-beta(1) concentration (P<0.01) at these sites; and (5) attenuated TGF-beta(1) and type I collagen gene express ion (P<0.01) at these sites in rats receiving losartan. These observat ions suggest locally generated AngII via AT(1) receptor binding is cor related to TGF-P, expression and synthesis at sites of repair and remo te sites in the infarcted rat heart. The mechanism responsible for the role of AngII in TGF-P, remains to be elucidated. (C) 1998 Academic P ress