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

Abstract

<p>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 <i>Atg7</i> in murine VSMCs (<i>atg7</i>^{<i>−/−</i>} 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 <i>Atg7</i>^<i>+/+</i> VSMCs induced similar features, suggesting that accumulation of SQSTM1 promotes VSMC senescence. Interestingly, <i>atg7</i>^{<i>−/−</i>} 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 <i>atg7</i> 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.</p