Nitric oxide attenuates the expression of transforming growth factor-β3 mRNA in rat cardiac fibroblasts via destabilization

Abstract

Transforming growth factor-β (TGF-β) 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-β 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-β3 mRNA levels, an effect mimicked by 8-bromo-cGMP. TGF-β3 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-β3, TGF-β1 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-β3 mRNA levels. By contrast, SNAP treatment caused a rapid decrease of TGF-β3 mRNA with a half-life of 3.3 ± 0.2 hours, thereby supporting a mechanism of destabilization. The pretreatment with SNAP inhibited angiotensin II-stimulated protein synthesis and the concomitant expression of TGF-β3 mRNA. These data reveal a disparate pattern of TGF-β1 and TGF-β3 mRNA regulation by NO and highlight a novel mechanism of destabilization contributing to the decreased expression of TGF-β3 mRNA. The modulation of both basal and angiotensin II-stimulated TGF-β3 mRNA expression provides a mechanism by which NO may influence the progression of interstitial fibrosis.