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

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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 Nω-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 1 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 T...

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