Abstract-Transforming growth factor-␤ (TGF-␤) has been implicated in the development of interstitial fibrosis in cardiac hypertrophy. NO has been regarded as a potent inhibitor of cardiac fibroblast growth, albeit the modulation of cellular events associated with interstitial fibrosis remains undefined. In this regard, the regulation of TGF-␤ mRNA expression by the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) was examined in neonatal rat cardiac fibroblasts. SNAP treatment for 4 hours decreased TGF-␤ 3 mRNA levels, an effect mimicked by 8-bromo-cGMP. TGF-␤ 3 mRNA, however, had returned to levels observed in the untreated cells after a 24-hour exposure to SNAP, whereas a decreased expression persisted with 8-bromo-cGMP. In contrast to TGF-␤ 3 , TGF-␤ 1 mRNA levels were modestly increased in response to cGMP-generating molecules. The treatment with actinomycin D for at least 8 hours did not appreciably alter TGF-␤ 3 mRNA levels. By contrast, SNAP treatment caused a rapid decrease of TGF-␤ 3 mRNA with a half-life of 3.3Ϯ0.2 hours, thereby supporting a mechanism of destabilization. The pretreatment with SNAP inhibited angiotensin II-stimulated protein synthesis and the concomitant expression of TGF-␤ 3 mRNA. These data reveal a disparate pattern of TGF-␤ 1 and TGF-␤ 3 mRNA regulation by NO and highlight a novel mechanism of destabilization contributing to the decreased expression of TGF-␤ 3 mRNA. The modulation of both basal and angiotensin II-stimulated TGF-␤ 3 mRNA expression provides a mechanism by which NO may influence the progression of interstitial fibrosis.

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