Moderate Autophagy Inhibits Vascular Smooth Muscle Cell Senescence to Stabilize Progressed Atherosclerotic Plaque via the mTORC1/ULK1/ATG13 Signal Pathway

Abstract

In order to investigate the effects of autophagy induced by rapamycin in the development of atherosclerosis plaque we established murine atherosclerosis model which was induced in ApoE−/− mice by high fat and cholesterol diet (HFD) for 16 weeks. Rapamycin and 3-Methyladenine (MA) were used as autophagy inducer and inhibitor respectively. The plaque areas in aortic artery were detected with HE and Oil Red O staining. Immunohistochemical staining were applied to investigate content of plaque respectively. In contrast to control and 3-MA groups, rapamycin could inhibit atherosclerosis progression. Rapamycin was able to increase collagen content and a-SMA distribution relatively, as well as decrease necrotic core area. Then we used MOVAS and culture with ox-LDL for 72 h to induce smooth muscle-derived foam cell model in vitro. Rapamycin and 3-MA were cultured together respectively. Flow cytometry assay and SA-β-Gal staining experiments were performed to detect survival and senescence of VSMCs. Western blot analysis were utilized to analyze the levels of protein expression. We found that rapamycin could promote ox-LDL-induced VSMCs autophagy survival and alleviate cellular senescence, in comparison to control and 3-MA groups. Western blot analysis showed that rapamycin could upregulate ULK1, ATG13 and downregulate mTORC1 and p53 protein expression.

Atorvastatin Inhibits Inflammatory Response, Attenuates Lipid Deposition, and Improves the Stability of Vulnerable Atherosclerotic Plaques by Modulating Autophagy

“…Defective autophagy in VSMCs (atg7 -/- VSMCs) accelerates senescence and promotes ligation-induced neointima formation and diet-induced atherogenesis, as shown by increased total collagen deposition, nuclear hypertrophy, CDKN2A upregulation, and GLB1 activity ( Grootaert et al, 2015 ). In contrast, rapamycin exerts anti-senescence effects in VSMCs via inhibition of the mTOR pathway ( Tan et al, 2016 ), which is known to be overactivated in senescent cells ( Luo et al, 2017 ). As in the vessel calcification, atorvastatin protects VSMCs from TGF-β1-stimulated calcification via autophagy activation ( Liu et al, 2014 ).…”

Rapamycin induces autophagy to alleviate acute kidney injury following cerebral ischemia and reperfusion via the mTORC1/ATG13/ULK1 signaling pathway

“…Cui et al ( 40 ) suggested that rapamycin may ameliorate gentamicin-induced AKI by enhancing autophagy in miniature pig models. Luo et al ( 41 ) identified that rapamycin inhibited vascular smooth muscle cell senescence via inducing autophagy. In the present study, it was identified that rapamycin pre-treatment prior to CIR attenuated renal pathological alterations and improved renal function, and the number of inflammatory cells around the renal tubules was significantly reduced in the rapamycin pre-treatment group compared with the CIR group.…”

Targeted elimination of senescent Ras-transformed cells by suppression of MEK/ERK pathway

“…The resistance partly develops due to autophagy, which provides the cells with a sufficient level of amino acids, thereby supporting high mTORC1 activity upon deprivation. However, persistent mTORC1 activity prevents senescent cells from the development of full autophagic program that is detrimental and leads to cell death [ 81 ] or attenuation of cellular senescence [ 70 , 82 ]. It is appropriate to add that re-localization of oncogenic Ras from the plasma membrane to the cytoplasm coincides in time with accumulation of damaged mitochondria.…”