Cited by 267Autophagy in Disease and TherapyAtherosclerosis and Cardiovascular DiseasesTelomeres, Telomerase, and Senescence

Defective autophagy in vascular smooth muscle cells accelerates senescence and promotes neointima formation and atherogenesis

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Grootaert, Mandy OJ, da Costa Martins, Paula A, Bitsch, Nicole, Pintelon, Isabel, De Meyer, Guido RY, Martinet, Wim, Schrijvers, Dorien M·2015·Autophagy

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 G1 proliferative 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.

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Authors
Grootaert, M. O., da Costa Martins, P. A., Bitsch, N., Pintelon, I., De Meyer, G. R., Martinet, W., & Schrijvers, D. M.
Affiliations
  • University of Antwerp (BE)
  • Department of Cardiology; Cardiovascular Research Institute Maastricht; Maastricht, The Netherlands
  • Maastricht University (NL)
  • Laboratory of Physiopharmacology; University of Antwerp; Antwerp, Belgium
Corresponding author
Schrijvers, Dorien M
Venue
Autophagy
Published
2015-11-02
Volume
11
Issue
11
Pages
2014-2032
ISSN
  • 1554-8627 (ISSN-L)
  • 1554-8635
OpenAlex
W2200751652
Cited by
267
References
73
Citations by year
2026: 8 · 2025: 20 · 2024: 22 · 2023: 28 · 2022: 28 · 2021: 35 · 2020: 30 · 2019: 31 · 2018: 33 · 2017: 19 · 2016: 13
FWCI
17.00
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Autophagy (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
  • Digital Access to Libraries (submittedVersion, other-oa)
Funders
  • Fonds Wetenschappelijk Onderzoek (G044312N)
  • Vlaamse regering
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
vascular smooth muscle cells, cellular senescence, neointima formation, atherosclerosis, ATG7, p62, stress-induced premature senescence, Nrf2, oxidative stress resistance, GLB1, MMP-9, CXCL12, collagen deposition

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