salicylates and Cardiomegaly

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.

Topics: Animals; Aspirin; Base Sequence; Cardiomegaly; DNA Primers; Electrophoretic Mobility Shift Assay; Immunoprecipitation; Male; NF-kappa B; Rats; Rats, Sprague-Dawley; RNA Processing, Post-Transcriptional; Salicylates; Signal Transduction

We have investigated the relationship between oxygen free radicals and acute rheumatic fever with regard to diagnosis of the disease process. At the time of diagnosis, we measured the levels of reactive oxygen molecules in the plasma, this being a parameter for oxygen free radicals, and discovered the levels to be significantly higher when compared with those measured in a control group (P<0.05). The levels measured in the plasma, however, were not statistically different among patients with and without carditis. We found a progressive decrease in the levels measured in the plasma when patients with acute rheumatic fever were tested on the 15th, 30th and 90th days subsequent to diagnosis. By the 90th day, levels measured in the plasma were still higher, but no longer significantly elevated, when compared with the control group. The present study is preliminary, but raises the possibility that measurement of oxygen free radicals in the plasma could be used as a laboratory test for active state of acute rheumatic fever. Further investigations will be needed, nonetheless, to determine the clinical application of this technique.

Topics: Acute Disease; Adolescent; Anti-Inflammatory Agents; Blood Sedimentation; C-Reactive Protein; Cardiomegaly; Child; Child Welfare; Electrocardiography; Female; Free Radicals; Humans; Male; Oxygen; Prednisolone; Radiography; Rheumatic Fever; Salicylates; Streptolysins; Turkey