Nuclear factor-κB 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)-kappa B 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 PPAR beta/delta involved in fatty acid utilization, and a fall in palmitate oxidation that was reversed by NF-kappa B inhibitors. Lipopolysaccharide stimulation of NF-kappa B in embryonic rat heart-derived H9c2 myotubes, which only express PPAR beta/delta, caused both a reduction in Pdk4 expression and DNA binding activity of PPAR beta/delta to its response element, effects that were reversed by NF-kappa B inhibitors. Coimmunoprecipitation studies demonstrated that lipopolysaccharide strongly stimulated the physical interaction between the p65 subunit of NF-kappa B and PPAR beta/delta, providing an explanation for the reduced activity of PPAR beta/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-kappa B and enhanced interaction between p65 and PPAR beta/delta. These results indicate that NF-kappa B activation during cardiac hypertrophy down-regulates PPAR beta/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-kappa B and PPAR beta/delta.