title: Defective autophagy in vascular smooth muscle cells accelerates senescence and promotes neointima formation and atherogenesis.
abstract: Autophagy is triggered in vascular smooth muscle cells (VSMCs) of diseased arterial vessels. However, the role of VSMC autophagy in cardiovascular disease is poorly understood. Therefore, we investigated the effect of defective autophagy on VSMC survival and phenotype and its significance in the development of postinjury neointima formation and atherosclerosis. Tissue-specific deletion of the essential autophagy gene Atg7 in murine VSMCs (atg7-/-VSMCs) caused accumulation of SQSTM1/p62 and accelerated the development of stress-induced premature senescence as shown by cellular and nuclear hypertrophy, CDKN2A-RB-mediated G1proliferative arrest and senescence-associated GLB1 activity. Transfection of SQSTM1-encoding plasmid DNA in Atg7+/+VSMCs induced similar features, suggesting that accumulation of SQSTM1 promotes VSMC senescence. Interestingly, atg7-/-VSMCs were resistant to oxidative stress-induced cell death as compared to controls. This effect was attributed to nuclear translocation of the transcription factor NFE2L2 resulting in upregulation of several antioxidative enzymes. In vivo, defective VSMC autophagy led to upregulation of MMP9, TGFB and CXCL12 and promoted postinjury neointima formation and diet-induced atherogenesis. Lesions of VSMC-specific atg7 knockout mice were characterized by increased total collagen deposition, nuclear hypertrophy, CDKN2A upregulation, RB hypophosphorylation, and GLB1 activity, all features typical of cellular senescence. To conclude, autophagy is crucial for VSMC function, phenotype, and survival. Defective autophagy in VSMCs accelerates senescence and promotes ligation-induced neointima formation and diet-induced atherogenesis, implying that autophagy inhibition as therapeutic strategy in the treatment of neointimal stenosis and atherosclerosis would be unfavorable. Conversely, stimulation of autophagy could be a valuable new strategy in the treatment of arterial disease.
authors.affiliation: a Laboratory of Physiopharmacology; University of Antwerp ; Antwerp , Belgium.
authors.forename: Mandy Oj
authors.initials: MO
authors.lastname: Grootaert
authors.affiliation: b Department of Cardiology ; Cardiovascular Research Institute Maastricht ; Maastricht , The Netherlands.
authors.forename: Paula A
authors.initials: PA
authors.lastname: da Costa Martins
authors.affiliation: b Department of Cardiology ; Cardiovascular Research Institute Maastricht ; Maastricht , The Netherlands.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bitsch
authors.affiliation: c Laboratory of Cell Biology and Histology; University of Antwerp ; Antwerp , Belgium.
authors.forename: Isabel
authors.initials: I
authors.lastname: Pintelon
authors.affiliation: a Laboratory of Physiopharmacology; University of Antwerp ; Antwerp , Belgium.
authors.forename: Guido Ry
authors.initials: GR
authors.lastname: De Meyer
authors.affiliation: a Laboratory of Physiopharmacology; University of Antwerp ; Antwerp , Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Martinet
authors.affiliation: a Laboratory of Physiopharmacology; University of Antwerp ; Antwerp , Belgium.
authors.forename: Dorien M
authors.initials: DM
authors.lastname: Schrijvers
keywords: atherosclerosis; autophagy; neointima formation; senescence; sequestosome 1/p62; vascular smooth muscle cells