title: Atorvastatin prevents peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) downregulation in lipopolysaccharide-stimulated H9c2 cells.
abstract: 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 (PPARbeta/delta in cardiac fatty acid metabolism, the aim of this study was to examine the effects of nuclear factor (NF)-kappaB 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 PPARbeta/delta-target gene pyruvatedehydrogenase kinase 4 (PDK4) that was prevented in the presence of the NF-kappaB inhibitors parthenolide (10 microM) and atorvastatin (10 microM). Electrophoretic mobility shift assay revealed that both parthenolide and atorvastatin significantly decreased LPS-stimulated NF-kappaB 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 PPARgamma 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. Co-immunoprecipitation studies showed that LPS-stimulation led to a reduction in the physical interaction between PGC-1 and PPARbeta/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 PPARbeta/delta binding activity in H9c2 cardiac cells. These results suggest that LPS-mediated NF-kappaB 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 PPARbeta/delta transactivation of target genes involved in cardiac fatty acid oxidation.
authors.affiliation: Unidad de Farmacología, Departamento de Farmacología y Química Terapéutica, Facultad de Farmacia, Universidad de Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Planavila
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Sánchez
authors.forename: Manuel
authors.initials: M
authors.lastname: Merlos
authors.forename: Juan C
authors.initials: JC
authors.lastname: Laguna
authors.forename: Manuel
authors.initials: M
authors.lastname: Vázquez-Carrera
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000069059:Atorvastatin; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D048068:PPAR-beta / Q000378:metabolism*; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D012717:Sesquiterpenes / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D000924:Anticholesteremic Agents; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D005227:Fatty Acids; D006538:Heptanoic Acids; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047495:PPAR gamma; D048068:PPAR-beta; D011758:Pyrroles; D012717:Sesquiterpenes; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; C002669:parthenolide; D000069059:Atorvastatin; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4