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: Lucas Ravaux, Chantal Denoyelle, Claire Monne, Isabelle Limon, Michel Raymondjean, Khadija El Hadri
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 27 Issue 23 Pg. 8374-87 (Dec 2007) ISSN: 1098-5549 [Electronic] United States
• PMID: 17908795 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-1beta
• Ligands
• PPAR-beta
• Proto-Oncogene Proteins c-bcl-6
• RNA, Messenger
• RNA, Small Interfering
• Repressor Proteins
• Retinoid X Receptors
• Group II Phospholipases A2

Topics

• Animals
• Cattle
• Enzyme Induction (drug effects)
• Gene Expression Regulation, Enzymologic (drug effects)
• Group II Phospholipases A2 (biosynthesis, genetics)
• Interleukin-1beta (pharmacology)
• Ligands
• Male
• Muscle, Smooth, Vascular (cytology, drug effects, enzymology)
• Myocytes, Smooth Muscle (drug effects, enzymology)
• PPAR-beta (metabolism)
• Protein Binding (drug effects)
• Proto-Oncogene Proteins c-bcl-6 (metabolism)
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering (metabolism)
• Rats
• Rats, Wistar
• Repressor Proteins (metabolism)
• Response Elements
• Retinoid X Receptors (metabolism)
• Sequence Deletion