Nuclear factor-kappaB activation leads to down-regulation of fatty acid oxidation during cardiac hypertrophy.
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.
Planavila
Anna
A
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, E-08028 Barcelona, Spain.
Laguna
Juan C
JC
Vázquez-Carrera
Manuel
M
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
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