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Abstract
Activation of nuclear factor-kappaB (NF-kappaB) 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 (PPARalpha) 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 beta-oxidation. In contrast, etomoxir treatment for 10 days dramatically decreased ACO mRNA levels by 96%. 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-kappaB 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-kappaB activation.
Highlights
Activation of nuclear factor-B (NF-B) is required for hypertrophic growth of cardiomyocytes
This direct repeat is known to Abbreviations: ACO, acyl-CoA oxidase; COUP-TF II, chicken ovalbumin upstream promoter transcription factor II; CTE, cytosolic acylCoA thioesterase; GPX, glutathione peroxidase; MCAD, medium-chain acyl-CoA dehydrogenase; muscle-type carnitine palmitoyl-transferase (M-carnitine palmitoyltransferase I (CPT-I)), muscle-type carnitine palmitoyltransferase; NF-B, nuclear factor B; PGC-1, PPAR␥ coactivator 1; PPAR, peroxisome proliferator-activated receptor; PPRE, peroxisome proliferator response element; RXR, retinoid X receptor; UCP-3, uncoupling protein 3
Our results show that during etomoxir-induced cardiac hypertrophy, there is a dramatic reduction in ACO mRNA that is accompanied by an increase in NF-B activity
Summary
Activation of nuclear factor-B (NF-B) is required for hypertrophic growth of cardiomyocytes. It has been shown that the energy substrate switch observed in cardiac hyperthrophy involves reactivation of fetal transcriptional control via members of the Sp and COUP-TF families of transcription factors [7] These changes may account for the down-regulation of enzymes involved in fatty acid oxidation. Treatment for 1 day with this drug, which in addition activates PPAR␣ [10], resulted in a significant increase in the mRNA expression of acyl-CoA oxidase (ACO), the gene that catalyzes the ratelimiting step in peroxisomal -oxidation. The negative correlation in heart between enhanced oxidative stress and the reduction ACO expression suggests that peroxisomal -oxidation may be involved in cardiac hypertrophy after etomoxir treatment
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