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

نویسندگان

  • Anna Planavila
  • Ricardo Rodríguez-Calvo
  • Alberto Fernández de Arriba
  • Rosa M Sánchez
  • Juan C Laguna
  • Manuel Merlos
  • Manuel Vazquez-Carrera
چکیده

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.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Inhibition of cyclooxygenase-2 expression by 4-trifluoromethyl derivatives of salicylate, triflusal, and its deacetylated metabolite, 2-hydroxy-4-trifluoromethylbenzoic acid.

The therapeutic potential of drugs that block the induction of cyclooxygenase-2 has been emphasized. When two 4-trifluoromethyl salicylate derivatives [2-acetoxy-4-trifluoromethyl-benzoic acid (triflusal) and its deacetylated metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB)] were compared with aspirin and sodium salicylate as cyclooxygenase-2 (COX-2) inhibitors, we observed that in bact...

متن کامل

QT dispersion in ischaemic heart disease.

[1] Maseri A 1995 Ischemic Heart Disease. New York: Churchill Livingstone Inc. [2] Knight CJ. New insights into the pathophysiology of acute coronary occlusion. Eur Heart J 1999; (Suppl F): F3–F6. [3] Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 92: 657–71. [4] Cairns JA. Antithrombotic agents in coronary artery disease. Chest 1998; 114: 611S–33S. [5] Trip MD, Cats V...

متن کامل

Pharmacokinetics, safety and tolerability of triflusal and its main active metabolite HTB in healthy Chinese subjects.

Triflusal presents comparable antiplatelet activity to aspirin while presenting a more favourable safety profile, and is used in the treatment of thrombosis. The study aimed to evaluate the pharmacokinetics and safety of triflusal and its major metabolite 2-(hydroxyl)-4-(trifluoromethyl)- benzoic acid (HTB) in healthy Chinese subjects.30 healthy subjects were recruited in this randomized, singl...

متن کامل

Photosensitivity to Triflusal: Formation of a Photoadduct with Ubiquitin Demonstrated by Photophysical and Proteomic Techniques

Triflusal is a platelet aggregation inhibitor chemically related to acetylsalicylic acid, which is used for the prevention and/or treatment of vascular thromboembolisms, which acts as a prodrug. Actually, after oral administration it is absorbed primarily in the small intestine, binds to plasma proteins (99%) and is rapidly biotransformed in the liver into its deacetylated active metabolite 2-h...

متن کامل

A new pharmacological effect of salicylates: inhibition of NFAT-dependent transcription.

The anti-inflammatory effects of salicylates, originally attributed to inhibition of cyclooxygenase activity, are currently known to involve additional mechanisms. In this study we investigated the possible modulation by salicylates of NFAT-mediated transcription in lymphocytic and monocytic cell lines. RNase protection assays showed that 2-acetoxy-4-trifluoromethylbenzoic acid (triflusal) inhi...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Molecular pharmacology

دوره 69 4  شماره 

صفحات  -

تاریخ انتشار 2006