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J. Biol. Chem., Vol. 280, Issue 17, 17464-17471, April 29, 2005

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Nuclear Factor-B Activation Leads to Down-regulation of Fatty Acid Oxidation during Cardiac Hypertrophy^*

Anna Planavila, Juan C. Laguna, and Manuel Vázquez-Carrera

From the Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, E-08028 Barcelona, Spain

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

Received for publication, December 17, 2004 , and in revised form, February 8, 2005.

^* This work was supported in part by grants from the Fundació Privada Catalana de Nutrició i Lipids, Fundación Ramón Areces, Grants SAF2003-01232 and SAF2004-03045 from the Ministerio de Ciencia y Tecnología of Spain, the European Union FEDER Funds, and Grant 2001SGR00141 from the Generalitat de Catalunya. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a grant from the Ministerio de Ciencia y Tecnología of Spain.

To whom correspondence should be addressed: Unitat de Farmacologia, Facultat de Farmàcia, Diagonal 643, E-08028 Barcelona, Spain. Tel.: 34-93-4024531; Fax: 34-93-4035982; E-mail: mvazquezcarrera{at}ub.edu.

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