title: Caveolae control the anti-inflammatory phenotype of senescent endothelial cells.
abstract: Senescent endothelial cells (EC) have been identified in cardiovascular disease, in angiogenic tumour associated vessels and in aged individuals. We have previously identified a novel anti-inflammatory senescent phenotype of EC. We show here that caveolae are critical in the induction of this anti-inflammatory senescent state. Senescent EC induced by either the overexpression of ARHGAP18/SENEX or by H₂O₂ showed significantly increased numbers of caveolae and associated proteins Caveolin-1, cavin-1 and cavin-2. Depletion of these proteins by RNA interference decreased senescence induced by ARHGAP18 and by H₂O₂. ARHGAP18 overexpression induced a predominantly anti-inflammatory senescent population and depletion of the caveolae-associated proteins resulted in the preferential reduction in this senescent population as measured by neutrophil adhesion and adhesion protein expression after TNFα treatment. In confirmation, EC isolated from the aortas of CAV-1(-/-) mice failed to induce this anti-inflammatory senescent cell population upon expression of ARHGAP18, whereas EC from wild-type mice showed a significant increase. NF-κB is one of the major transcription factors mediating the induction of E-selectin and VCAM-1 expression, adhesion molecules responsible for leucocyte attachment to EC. TNFα-induced activation of NF-κB was suppressed in ARHGAP18-induced senescent EC, and this inhibition was reversed by Caveolin-1 knock-down. Thus, out results demonstrate that an increase in caveolae and its component proteins in senescent ECs is associated with inhibition of the NF-kB signalling pathway and promotion of the anti-inflammatory senescent pathway.
authors.affiliation: Centre for the Endothelium, Vascular Biology Program, Centenary Institute, Sydney, Australia; The University of Sydney, NSW, 2006, Australia.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Powter
authors.forename: Paul R
authors.initials: PR
authors.lastname: Coleman
authors.forename: Mai H
authors.initials: MH
authors.lastname: Tran
authors.forename: Angelina J
authors.initials: AJ
authors.lastname: Lay
authors.forename: Patrick
authors.initials: P
authors.lastname: Bertolino
authors.forename: Robert G
authors.initials: RG
authors.lastname: Parton
authors.forename: Mathew A
authors.initials: MA
authors.lastname: Vadas
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Gamble
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D021941:Caveolae / Q000378:metabolism*; D051242:Caveolin 1 / Q000378:metabolism; D016922:Cellular Senescence; D020690:GTPase-Activating Proteins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D028044:Phosphate-Binding Proteins; D016601:RNA-Binding Proteins / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C542464:ARHGAP18 protein, human; D000893:Anti-Inflammatory Agents; C497835:CAVIN1 protein, human; C112303:CAVIN2 protein, human; D002352:Carrier Proteins; D051242:Caveolin 1; D020690:GTPase-Activating Proteins; D016328:NF-kappa B; D028044:Phosphate-Binding Proteins; D016601:RNA-Binding Proteins; D018808:Transcription Factor AP-1
keywords: ARHGAP18; caveolae; cellular senescence; endothelial cells; inflammation