Showing papers by "Angelino Calderone published in 2001"

Long-Term Effects of Nonselective Endothelin A and B Receptor Antagonism in Postinfarction Rat Importance of Timing

Abstract: Background Some controversy exists as to the effects of endothelin (ET) receptor antagonism on long-term post–myocardial infarction (MI) evolution, particularly as it relates to the timing of the intervention after MI (<24 hours versus 10 days). Methods and Results Sham rats and rats surviving an acute MI for >20 hours (n=301) were assigned to treatment with saline or the nonselective ETA and ETB receptor antagonist LU 420627 (LU) started <24 hours (early) or 10 days (late) after MI and continued for 100 days. Long-term LU treatment led to increased mortality of rats with large MI, regardless of the timing of initiation of therapy. Early initiation of LU reduced survival from 61% to 16% ( P <0.001 versus untreated), and later initiation reduced survival to 36% ( P =0.012 versus untreated and P <0.001 versus early initiation). Early initiation of LU led to scar thinning, further left ventricular (LV) dilatation, LV dysfunction, and an excessive rise in right ventricular systolic pressure. Later initiation of LU did not modify scar formation but resulted in LV dilatation and dysfunction compared with the untreated group. Cardiac fibrosis tended to increase in the LU-treated MI groups. LU in the sham group reduced cardiac endothelial constitutive nitric oxide synthase but did not modify the changes that occurred with a large MI. Conclusions The use of the nonselective ETA and ETB receptor antagonist LU results in reduced survival, ventricular dilatation, and dysfunction whether started early or late after MI. Early initiation of LU resulted in scar expansion and a particularly unfavorable outcome. Received May 17, 2001; revision received July 23, 2001; accepted July 31, 2001.

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-β 3 mRNA levels, an effect mimicked by 8-bromo-cGMP. TGF-β 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-β 3 , TGF-β 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-β 3 mRNA levels. By contrast, SNAP treatment caused a rapid decrease of TGF-β 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-β 3 mRNA. These data reveal a disparate pattern of TGF-β 1 and TGF-β 3 mRNA regulation by NO and highlight a novel mechanism of destabilization contributing to the decreased expression of TGF-β 3 mRNA. The modulation of both basal and angiotensin II-stimulated TGF-β 3 mRNA expression provides a mechanism by which NO may influence the progression of interstitial fibrosis.

TGF-β1 and prepro-ANP mRNAs are differentially regulated in exercise-induced cardiac hypertrophy

Abstract: The induction of transforming growth factor (TGF)-β and prepro-atrial natriuretic peptide (ANP) mRNAs represent hallmark features of pathological cardiac hypertrophy. The present study examined whe...