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Molecular and Cellular Biology, December 2007, p. 8374-8387, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00623-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Inhibition of Interleukin-1ß-Induced Group IIA Secretory Phospholipase A2 Expression by Peroxisome Proliferator-Activated Receptors (PPARs) in Rat Vascular Smooth Muscle Cells: Cooperation between PPARß and the Proto-Oncogene BCL-6{triangledown}

Lucas Ravaux, Chantal Denoyelle, Claire Monne, Isabelle Limon, Michel Raymondjean,* and Khadija El Hadri

UMR Physiologie et Physiopathologie, Université Pierre et Marie Curie, CNRS, 7 quai Saint-Bernard, 75252 Paris, France

Received 10 April 2007/ Returned for modification 14 May 2007/ Accepted 18 September 2007

The inflammation that occurs during atherosclerosis is characterized by the release of large amounts of group IIA secretory phospholipase A2 (sPLA2-IIA). This study was designed to define the function of the three peroxisome proliferator-activated receptors (PPARs) on sPLA2 expression in vascular smooth muscle cells (VSMCs). We found that PPAR ligands decreased sPLA2-IIA activity and inhibited mRNA accumulation under inflammatory conditions. Furthermore, interleukin-1ß-induced sPLA2-IIA promoter activity was inhibited by the three PPAR ligands and in a similar way when cells were cotransfected with PPAR{alpha}, PPARß, or PPAR{gamma}, plus retinoid X receptor {alpha} (RXR{alpha}). Our study revealed that the regulation of sPLA2-IIA gene transcription by PPAR{alpha}/RXR and PPAR{gamma}/RXR heterodimers requires an interaction with a PPAR response element (PPRE) of the sPLA2-IIA promoter. In contrast, PPARß operates through a PPRE-independent mechanism. In addition, we demonstrated that VSMCs expressed the transcriptional repressor BCL-6. Overexpression of BCL-6 markedly reduced sPLA2-IIA promoter activity in VSMCs, while a dominant negative form of BCL-6 abrogated sPLA2 repression by PPARß. The PPARß agonist induced a BCL-6 binding to the sPLA2 promoter in VSMCs under inflammatory conditions. The knockdown of BCL-6 by short interfering RNA abolished the inhibitory effect of the PPARß ligand on sPLA2 activity and prostaglandin E2 release. Thus, the inhibition of sPLA2-IIA activity by PPARß agonists may provide a promising approach to impacting the initiation and progression of atherosclerosis.

* Corresponding author. Mailing address: Université Pierre et Marie Curie (Paris 6) UMR CNRS 7079-Physiologie et Physiopathologie-Université Pierre et Marie Curie 7, quai Saint-Bernard, Bât. A, 5° étage, boîte 256, 75252 Paris Cedex 05, France. Phone: 33 1 44 27 32 05. Fax: 33 1 44 27 51 40. E-mail: michel.raymondjean{at}snv.jussieu.fr

{triangledown} Published ahead of print on 1 October 2007.

Molecular and Cellular Biology, December 2007, p. 8374-8387, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00623-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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