title: AMPK Signaling Involvement for the Repression of the IL-1β-Induced Group IIA Secretory Phospholipase A2 Expression in VSMCs.
abstract: Secretory Phospholipase A2 of type IIA (sPLA2 IIA) plays a crucial role in the production of lipid mediators by amplifying the neointimal inflammatory context of the vascular smooth muscle cells (VSMCs), especially during atherogenesis. Phenformin, a biguanide family member, by its anti-inflammatory properties presents potential for promoting beneficial effects upon vascular cells, however its impact upon the IL-1β-induced sPLA2 gene expression has not been deeply investigated so far. The present study was designed to determine the relationship between phenformin coupling AMP-activated protein kinase (AMPK) function and the molecular mechanism by which the sPLA2 IIA expression was modulated in VSMCs. Here we find that 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleotide (AICAR) treatment strongly repressed IL-1β-induced sPLA2 expression at least at the transcriptional level. Our study reveals that phenformin elicited a dose-dependent inhibition of the sPLA2 IIA expression and transient overexpression experiments of constitutively active AMPK demonstrate clearly that AMPK signaling is involved in the transcriptional inhibition of sPLA2-IIA gene expression. Furthermore, although the expression of the transcriptional repressor B-cell lymphoma-6 protein (BCL-6) was markedly enhanced by phenformin and AICAR, the repression of sPLA2 gene occurs through a mechanism independent of BCL-6 DNA binding site. In addition we show that activation of AMPK limits IL-1β-induced NF-κB pathway activation. Our results indicate that BCL-6, once activated by AMPK, functions as a competitor of the IL-1β induced NF-κB transcription complex. Our findings provide insights on a new anti-inflammatory pathway linking phenformin, AMPK and molecular control of sPLA2 IIA gene expression in VSMCs.
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, Biological Adaptation and Ageing (B2A) CNRS UMR8256/INSERM ERL-U1064, F-75005 Paris, France.
authors.forename: Khadija
authors.initials: K
authors.lastname: El Hadri
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, BFA CNRS UMR8251, 4 Rue MA Lagroua Weill Hallé, 75013 Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Denoyelle
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, Biological Adaptation and Ageing (B2A) CNRS UMR8256/INSERM ERL-U1064, F-75005 Paris, France.
authors.forename: Lucas
authors.initials: L
authors.lastname: Ravaux
authors.affiliation: Institut Cochin, Inserm U1016, Paris, France; CNRS, UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Institut Cochin, Inserm U1016, Paris, France; CNRS, UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, Biological Adaptation and Ageing (B2A) CNRS UMR8256/INSERM ERL-U1064, F-75005 Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Friguet
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, Biological Adaptation and Ageing (B2A) CNRS UMR8256/INSERM ERL-U1064, F-75005 Paris, France.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Rouis
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, Biological Adaptation and Ageing (B2A) CNRS UMR8256/INSERM ERL-U1064, F-75005 Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Raymondjean
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002469:Cell Separation; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D054501:Group II Phospholipases A2 / Q000235:genetics* / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism; D010629:Phenformin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D021122:Protein Subunits / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D021122:Protein Subunits; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D010629:Phenformin; D055372:AMP-Activated Protein Kinases; D054501:Group II Phospholipases A2; C031143:AICA ribonucleotide