Nitric oxide attenuates the expression of transforming growth factor-beta(3) mRNA in rat cardiac fibroblasts via destabilization

Transforming growth factor-beta (TGF-beta) has been implicated in the devel opment of interstitial fibrosis in cardiac hypertrophy. NO has been regarde d 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-beta mRNA expression by the NO dono r S-nitroso-N-acetyl-penicillamine (SNAP) was examined in neonatal rat card iac fibroblasts. SNAP treatment for 4 hours decreased TGF-beta (3) mRNA lev els, an effect mimicked by 8-bromo-cGMP. TGF-beta (3) mRNA, however, had re turned to levels observed in the untreated cells after a 24-hour exposure t o SNAP, whereas a decreased expression persisted with 8-bromo-cGMP. In cont rast to TGF-beta (3), TGF-beta (1) mRNA levels were modestly increased in r esponse to cGMP-generating molecules. The treatment with actinomycin D for at least 8 hours did not appreciably alter TGF-beta (3) mRNA levels. By con trast, SNAP treatment caused a rapid decrease of TGF-beta (3) mRNA with a h alf-life of 3.3 +/-0.2 hours, thereby supporting a mechanism of destabiliza tion. The pretreatment with SNAP inhibited angiotensin II-stimulated protei n synthesis and the concomitant expression of TGF-beta (3) mRNA. These data reveal a disparate pattern of TGF-beta (1) and TGF-beta (3) mRNA regulatio n by NO and highlight a novel mechanism of destabilization contributing to the decreased expression of TGF-beta (3) mRNA. The modulation of both basal and angiotensin II-stimulated TGF-beta (3) mRNA expression provides a mech anism by which NO may influence the progression of interstitial fibrosis.