Angiotensin II, transforming growth factor-β1 and repair in the infarcted heart

Tissue repair following myocardial infarction (MI) eventuates in fibrous tissue formation at the site of myocyte necrosis. Following a large transmural MT, fibrosis appears remote to the infarct site. This is associated with extensive tissue remodeling that adversely affects ventricular diastolic function. Substances involved in promoting fibrous tissue formation at MI and remote sites are under investigation. Angiotensin II (AngII), generated at sites of repair, has been implicated. However, its regulatory role on fibrous tissue formation remains uncertain. In the present study we sought to determine whether AngII is correlated to transforming growth factor beta 1 (TGF-beta(1)) expression, a regulator of fibrous tissue formation, at these sites of tissue repair. Mie studied: (1) localization and expression of angiotensin converting 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) synthesis by chronic blockade of AT(1) receptors began at the time of surgery 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 binding 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 and fibrosis of intraventricular septum, interstitial fibrosis of noninfarcted 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 expression (P<0.01) at these sites in rats receiving losartan. These observations suggest locally generated AngII via AT(1) receptor binding is correlated to TGF-P, expression and synthesis at sites of repair and remote sites in the infarcted rat heart. The mechanism responsible for the role of AngII in TGF-P, remains to be elucidated. (C) 1998 Academic Press