Inhibition of cardiac hypertrophy by triflusal (4-trifluoromethyl derivative of salicylate) and its active metabolite.

Abstract

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.

• Authors: Anna Planavila, Ricardo Rodríguez-Calvo, Alberto Fernández de Arriba, Rosa M Sánchez, Juan C Laguna, Manuel Merlos, Manuel Vazquez-Carrera
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 69 Issue 4 Pg. 1174-81 (Apr 2006) ISSN: 0026-895X [Print] United States
• PMID: 16421291 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• NF-kappa B
• Salicylates
• triflusal
• Aspirin

Topics

• Animals
• Aspirin (pharmacology)
• Base Sequence
• Cardiomegaly (prevention & control)
• DNA Primers
• Electrophoretic Mobility Shift Assay
• Immunoprecipitation
• Male
• NF-kappa B (antagonists & inhibitors, metabolism)
• RNA Processing, Post-Transcriptional
• Rats
• Rats, Sprague-Dawley
• Salicylates (pharmacology, therapeutic use)
• Signal Transduction