title: Senescent Vascular Smooth Muscle Cells Drive Inflammation Through an Interleukin-1α-Dependent Senescence-Associated Secretory Phenotype.
abstract: OBJECTIVE
  Vascular smooth muscle cells (VSMCs) that become senescent are both present within atherosclerotic plaques and thought to be important to the disease process. However, senescent VSMCs are generally considered to only contribute through inaction, with failure to proliferate resulting in VSMC- and collagen-poor unstable fibrous caps. Whether senescent VSMCs can actively contribute to atherogenic processes, such as inflammation, is unknown.
  
  
  RESULTS
  We find that senescent human VSMCs develop a proinflammatory state known as a senescence-associated secretory phenotype. Senescent human VSMCs release high levels of multiple cytokines and chemokines driven by secreted interleukin-1α acting in an autocrine manner. Consequently, the VSMC senescence-associated secretory phenotype promotes chemotaxis of mononuclear cells in vitro and in vivo. In addition, senescent VSMCs release active matrix metalloproteinase-9, secrete less collagen, upregulate multiple inflammasome components, and prime adjacent endothelial cells and VSMCs to a proadhesive and proinflammatory state. Importantly, maintaining the senescence-associated secretory phenotype places a large metabolic burden on senescent VSMCs, such that they can be selectively killed by inhibiting glucose utilization.
  
  
  CONCLUSIONS
  Senescent VSMCs may actively contribute toward the chronic inflammation associated with atherosclerosis through the interleukin-1α-driven senescence-associated secretory phenotype and the priming of adjacent cells to a proatherosclerotic state. These data also suggest that inhibition of this potentially important source of chronic inflammation in atherosclerosis requires blockade of interleukin-1α and not interleukin-1β.
authors.affiliation: From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Gardner
authors.affiliation: From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Melanie
authors.initials: M
authors.lastname: Humphry
authors.affiliation: From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Bennett
authors.affiliation: From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom. mchc2@cam.ac.uk.
authors.forename: Murray C H
authors.initials: MC
authors.lastname: Clarke
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053582:Interleukin-1alpha / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000235:genetics*; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D053582:Interleukin-1alpha; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D012313:RNA
keywords: aging; atherosclerosis; inflammation; interleukin-1; muscle, smooth, vascular