title: Nitric oxide attenuates the expression of transforming growth factor-beta(3) mRNA in rat cardiac fibroblasts via destabilization.
abstract: Transforming growth factor-beta (TGF-beta) 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-beta 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-beta(3) mRNA levels, an effect mimicked by 8-bromo-cGMP. TGF-beta(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-beta(3), TGF-beta(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-beta(3) mRNA levels. By contrast, SNAP treatment caused a rapid decrease of TGF-beta(3) 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-beta(3) mRNA. These data reveal a disparate pattern of TGF-beta(1) and TGF-beta(3) mRNA regulation 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 mechanism by which NO may influence the progression of interstitial fibrosis.
authors.affiliation: Université de Montréal, Departemént de Physiologie, et l'Institut de Cardiologie de Montréal, Montréal, Québec, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Abdelaziz
authors.forename: F
authors.initials: F
authors.lastname: Colombo
authors.forename: I
authors.initials: I
authors.lastname: Mercier
authors.forename: A
authors.initials: A
authors.lastname: Calderone
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000494:pharmacology; D004336:Drug Antagonism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D009206:Myocardium / Q000166:cytology*; D009569:Nitric Oxide / Q000502:physiology*; D010396:Penicillamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D020871:RNA Stability; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D026423:S-Nitroso-N-Acetylpenicillamine; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics*; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3
chemical_list: D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; C509046:Tgfb3 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3; D000804:Angiotensin II; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D010396:Penicillamine; D006152:Cyclic GMP