title: Inhibition of interleukin-1beta-induced group IIA secretory phospholipase A2 expression by peroxisome proliferator-activated receptors (PPARs) in rat vascular smooth muscle cells: cooperation between PPARbeta and the proto-oncogene BCL-6.
abstract: 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-1beta-induced sPLA2-IIA promoter activity was inhibited by the three PPAR ligands and in a similar way when cells were cotransfected with PPARalpha, PPARbeta, or PPARgamma, plus retinoid X receptor alpha (RXRalpha). Our study revealed that the regulation of sPLA2-IIA gene transcription by PPARalpha/RXR and PPARgamma/RXR heterodimers requires an interaction with a PPAR response element (PPRE) of the sPLA2-IIA promoter. In contrast, PPARbeta 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 PPARbeta. The PPARbeta 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 PPARbeta ligand on sPLA2 activity and prostaglandin E2 release. Thus, the inhibition of sPLA2-IIA activity by PPARbeta agonists may provide a promising approach to impacting the initiation and progression of atherosclerosis.
authors.affiliation: UMR Physiologie et Physiopathologie, Université Pierre et Marie Curie, CNRS, 7 quai Saint-Bernard, 75252 Paris, France.
authors.forename: Lucas
authors.initials: L
authors.lastname: Ravaux
authors.forename: Chantal
authors.initials: C
authors.lastname: Denoyelle
authors.forename: Claire
authors.initials: C
authors.lastname: Monne
authors.forename: Isabelle
authors.initials: I
authors.lastname: Limon
authors.forename: Michel
authors.initials: M
authors.lastname: Raymondjean
authors.forename: Khadija
authors.initials: K
authors.lastname: El Hadri
mesh_terms: D000818:Animals; D002417:Cattle; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D054501:Group II Phospholipases A2 / Q000096:biosynthesis* / Q000235:genetics; D053583:Interleukin-1beta / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology*; D048068:PPAR-beta / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000378:metabolism; D020218:Response Elements; D047488:Retinoid X Receptors / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: D053583:Interleukin-1beta; D008024:Ligands; D048068:PPAR-beta; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D054501:Group II Phospholipases A2