Early induction of transforming growth factor-β via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats

Abstract

We previously reported that the chronic inhibition of nitric oxide (NO) synthesis increases cardiac tissue angiotensin-converting enzyme expression and causes cardiac fibrosis in rats. However, the mechanisms are not known. Transforming growth factor-β (TGF-β) is a key molecule that is responsible for tissue fibrosis. The present study investigated the role of TGF-β in the pathogenesis of cardiac fibrosis. The development of cardiac fibrosis by oral administration of the NO synthesis inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) to normal rats was preceded by increases in mRNA levels of cardiac TGF-β1 and extracellular matrix (ECM) proteins. TGF-β immunoreactivity was increased in the areas of fibrosis. Treatment with a specific angiotensin II type I receptor antagonist, but not with hydralazine, completely prevented the L-NAME-induced increases in the gene expression of TGF-β1 and ECM proteins and also prevented cardiac fibrosis. Intraperitoneal injection of neutralizing antibody against TGF-β did not affect the L-NAME-induced increase in TGF-β1 mRNA levels but prevented an increase in the mRNA levels of ECM protein. These results suggest that the early induction of TGF-β via the angiotensin II type 1 receptor plays a major role in the development of cardiac fibrosis in this model.