Treatment with a specific angiotensin II type 1 receptor antagonist completely prevented L-NAME-induced increases in TGF-beta1 and extracellular matrix protein gene expression and cardiac fibrosis.
Does angiotensin II type 1 receptor blockade or TGF-beta neutralization prevent cardiac fibrosis in rats with chronic NO synthesis inhibition?
Early induction of TGF-beta1 via the angiotensin II type 1 receptor plays a major role in the development of cardiac fibrosis induced by chronic NO synthesis inhibition in rats.
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-beta (TGF-beta) is a key molecule that is responsible for tissue fibrosis. The present study investigated the role of TGF-beta in the pathogenesis of cardiac fibrosis. The development of cardiac fibrosis by oral administration of the NO synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) to normal rats was preceded by increases in mRNA levels of cardiac TGF-beta1 and extracellular matrix (ECM) proteins. TGF-beta immunoreactivity was increased in the areas of fibrosis. Treatment with a specific angiotensin II type 1 receptor antagonist, but not with hydralazine, completely prevented the L-NAME-induced increases in the gene expression of TGF-beta1 and ECM proteins and also prevented cardiac fibrosis. Intraperitoneal injection of neutralizing antibody against TGF-beta did not affect the L-NAME-induced increase in TGF-beta1 mRNA levels but prevented an increase in the mRNA levels of ECM protein. These results suggest that the early induction of TGF-beta1 via the angiotensin II type 1 receptor plays a major role in the development of cardiac fibrosis in this model.
Tomita et al. (Sat,) conducted a other in Cardiac fibrosis. Angiotensin II type 1 receptor antagonist and neutralizing antibody against TGF-beta vs. Hydralazine was evaluated on Cardiac fibrosis and mRNA levels of TGF-beta1 and extracellular matrix proteins. Treatment with a specific angiotensin II type 1 receptor antagonist completely prevented L-NAME-induced increases in TGF-beta1 and extracellular matrix protein gene expression and cardiac fibrosis.