The nuclear factor (
NF)-kappaB signaling pathway is an important intracellular mediator of
cardiac hypertrophy. The aim of the present study was to determine whether
triflusal (2-acetoxy-4-trifluoromethylbenzoic acid), a
salicylate derivative used as
antiplatelet agent, and its active metabolite
2-hydroxy-4-trifluoromethylbenzoic acid (
HTB) inhibit
cardiac hypertrophy in vitro and in vivo by blocking the
NF-kappaB signaling pathway. In cultured neonatal rat cardiomyocytes,
HTB (300 microM, a concentration reached in clinical use) inhibited
phenylephrine (PE)-induced
protein synthesis ([3H]
leucine uptake), induction of the fetal-type gene
atrial natriuretic factor (
ANF), and sarcomeric disorganization. Assessment of the effects of
triflusal in pressure overload-induced
cardiac hypertrophy by aortic banding resulted in a significant reduction in the ratio of heart weight to
body weight and in a reduction of the
mRNA levels of the
cardiac hypertrophy markers
ANF and
alpha-actinin compared with untreated banded rats. Electrophoretic mobility shift assay revealed an increase in the
NF-kappaB binding activity in cardiac nuclear extracts of banded rats that was prevented by
triflusal treatment. It is noteworthy that banded rats treated with oral
triflusal, compared with untreated rats, showed enhanced
protein levels of
IkappaBalpha, which forms a cytoplasmic inactive complex with the p65-p50 heterodimeric complex. Finally,
HTB increased phospho-
IkappaBalpha levels in neonatal cardiomyocytes and inhibited proteosome activity, suggesting that this
drug prevented proteosome-mediated degradation of
IkappaBalpha. These results indicate that
triflusal, a
drug with a well characterized pharmacological and safety profile currently used as antiplatelet, inhibits cardiomyocyte growth by interfering with the
NF-kappaB signaling pathway through a post-transcriptional mechanism involving reduced-proteosome degradation of
IkappaBalpha.