title: Nuclear factor-kappaB activation leads to down-regulation of fatty acid oxidation during cardiac hypertrophy.
abstract: Little is known about the mechanisms responsible for the fall in fatty acid oxidation during the development of cardiac hypertrophy. We focused on the effects of nuclear factor (NF)-kappaB activation during cardiac hypertrophy on the activity of peroxisome proliferator-activated receptor (PPAR) beta/delta, which is the predominant PPAR subtype in cardiac cells and plays a prominent role in the regulation of cardiac lipid metabolism. Phenylephrine-induced cardiac hypertrophy in neonatal rat cardiomyocytes caused a reduction in the expression of pyruvate dehydrogenase kinase 4 (Pdk4), a target gene of PPARbeta/delta involved in fatty acid utilization, and a fall in palmitate oxidation that was reversed by NF-kappaB inhibitors. Lipopolysaccharide stimulation of NF-kappaB in embryonic rat heart-derived H9c2 myotubes, which only express PPARbeta/delta, caused both a reduction in Pdk4 expression and DNA binding activity of PPARbeta/delta to its response element, effects that were reversed by NF-kappaB inhibitors. Coimmunoprecipitation studies demonstrated that lipopolysaccharide strongly stimulated the physical interaction between the p65 subunit of NF-kappaB and PPARbeta/delta, providing an explanation for the reduced activity of PPARbeta/delta. Finally, we assessed whether this mechanism was present in vivo in pressure overload-induced cardiac hypertrophy. In hypertrophied hearts of banded rats the reduction in the expression of Pdk4 was accompanied by activation of NF-kappaB and enhanced interaction between p65 and PPARbeta/delta. These results indicate that NF-kappaB activation during cardiac hypertrophy down-regulates PPARbeta/delta activity, leading to a fall in fatty acid oxidation, through a mechanism that involves enhanced protein-protein interaction between the p65 subunit of NF-kappaB and PPARbeta/delta.
authors.affiliation: Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, E-08028 Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Planavila
authors.forename: Juan C
authors.initials: JC
authors.lastname: Laguna
authors.forename: Manuel
authors.initials: M
authors.lastname: Vázquez-Carrera
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism*; D006321:Heart / Q000196:embryology; D006984:Hypertrophy; D015151:Immunoblotting; D047468:Immunoprecipitation; D050356:Lipid Metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D008297:Male; D009206:Myocardium / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D047494:PPAR delta / Q000378:metabolism; D048068:PPAR-beta / Q000378:metabolism; D010656:Phenylephrine / Q000737:chemistry; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005227:Fatty Acids; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047494:PPAR delta; D048068:PPAR-beta; D012333:RNA, Messenger; D010656:Phenylephrine; D004247:DNA; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D010100:Oxygen