Down-regulation of Acyl-CoA oxidase gene expression and increased nuclear factor-kB activity in etomoxir-induced cardiac hypertrophy

Àgatha Cabrero, Manuel Merlos, Juan C. Laguna, and Manuel Vázquez Carrera

Pharmacology and Therapeutical Chemistry, University of Barcelona, Barcelona E-08028

Corresponding Author: mvaz{at}farmacia.far.ub.es

Activation of nuclear factor-kB (NF-kB) is required for hypertrophic growth of cardiomyocytes. Etomoxir is an irreversible inhibitor of carnitine palmitoyltransferase I (CPT-I) that activates peroxisome proliferator-activated receptor alpha and induces cardiac hypertrophy through an unknown mechanism. We studied the mRNA expression of genes involved in fatty acid oxidation in the heart of mice treated for 1 or 10 days with etomoxir (100 mg/kg/day). Etomoxir administration for 1 day significantly increased (4.4-fold induction) the mRNA expression of acyl-CoA oxidase (ACO), which catalyzes the rate-limiting step in peroxisomal b-oxidation. In contrast, etomoxir treatment for 10 days dramatically decreased ACO mRNA levels by 96%. The mRNA expression of PPARa and several of its target were not altered in heart after 10 days of treatment with this drug. DNA binding activity of cardiac nuclear proteins to a consensus peroxisome proliferator response element (PPRE) probe was strongly induced in 10 days but not in 1 day etomoxir-treated mice as demonstrated by gel mobility shift assays. Interestingly, drug treatment increased chicken ovalbumin upstream promoter transcription factor II (COUP-TF II) protein levels in the heart of 10 days, but not in 1 day etomoxir-treated mice, in a negative correlation with ACO mRNA levels. However, antibody supershift studies did not show enhanced binding of this transcriptional repressor to the PPRE probe in the specific complexes from 10-day etomoxir-treated mice. The reduction in ACO expression in the hearts of 10-day etomoxir-treated mice was accompanied by an increase in the mRNA expression of the antioxidant enzyme glutathione peroxidase and the cardiac marker of oxidative stress bax. Moreover, the activity of the redox-regulated transcription factor NF-kB was increased in heart after 10 days of etomoxir treatment. Overall, the findings here presented show that etomoxir treatment may induce cardiac hypertrophy via increased cellular oxidative stress and NF-kB activation.

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