Atorvastatin prevents peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) downregulation in lipopolysaccharide-stimulated H9c2 cells

Although abnormalities in cardiac fatty acid metabolism are involved in the development of several cardiac pathologies, the mechanisms underlying these changes are not well understood. Given the prominent role played by peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta in cardiac fatty acid metabolism, the aim of this study was to examine the effects of nuclear factor (NF)-kappa B activation on the activity of this nuclear receptor. Embryonic rat heart-derived H9c2 cells stimulated with lipopolysaccharide (LPS) showed a reduction (38%, P<0.05) in the mRNA levels of the PPAR beta/delta-target gene pyruvatedehydrogenase kinase 4 (PDK4) that was prevented in the presence of the NF-kappa B inhibitors parthenolide (10 mu M) and atorvastatin (10 mu M). Electrophoretic mobility shift assay revealed that both parthenolide and atorvastatin significantly decreased LPS-stimulated NF-kappa B binding activity in H9c2 cardiac cells. LPS-stimulation of H9c2 cardiac cells also led to a 30% reduction (P<0.05) in the mRNA levels of PPAR gamma Coactivator 1 (PGC-1) that was consistent with the reduction in the protein levels of this coactivator. In the presence of either atorvastatin or parthenolide, the reduction in PGC-1 expression was prevented. Coimmunoprecipitation studies showed that LPS-stimulation led to a reduction in the physical interaction between PGC-1 and PPAR beta/delta and that this reduction was prevented in the presence of atorvastatin. Finally, electrophoretic mobility shift assay revealed that parthenolide and atorvastatin prevented LPS-mediated reduction in PPAR beta/delta binding activity in H9c2 cardiac cells. These results suggest that LPS-mediated NF-kappa B activation inhibits the expression of genes involved in fatty acid metabolism by a mechanism involving reduced expression of PGC-1, which in turn affects the PPAR beta/delta transactivation of target genes involved in cardiac fatty acid oxidation. (c) 2005 Elsevier B.V. All rights reserved.