Defective autophagy in vascular smooth muscle cells enhances cell death and atherosclerosis

Autophagy. 2018;14(11):1991-2006. doi: 10.1080/15548627.2018.1501132. Epub 2018 Aug 10.

Abstract

Macroautophagy/autophagy is considered as an evolutionarily conserved cellular catabolic process. In this study, we aimed to elucidate the role of autophagy in vascular smooth muscle cells (SMCs) on atherosclerosis. SMCs cultured from mice with SMC-specific deletion of the essential autophagy gene atg7 (Atg7cKO) showed reduced serum-induced cell growth, increased cell death, and decreased cell proliferation rate. Furthermore, 7-ketocholestrerol enhanced apoptosis and the expression of CCL2 (chemokine [C-C motif] ligand 2) with the activation of TRP53, the mouse ortholog of human and rat TP53, in SMCs from Atg7cKO mice. In addition, Atg7cKO mice crossed with Apoe (apolipoprotein E)-deficient mice (apoeKO; Atg7cKO:apoeKO) showed reduced medial cellularity and increased TUNEL-positive cells in the descending aorta at 10 weeks of age. Intriguingly, Atg7cKO: apoeKO mice fed a Western diet containing 1.25% cholesterol for 14 weeks showed a reduced survival rate. Autopsy of the mice demonstrated the presence of aortic rupture. Analysis of the descending aorta in Atg7cKO:apoeKO mice showed increased plaque area, increased TUNEL-positive area, decreased SMC-positive area, accumulation of macrophages in the media, and adventitia and perivascular tissue, increased CCL2 expression in SMCs in the vascular wall, medial disruption, and aneurysm formation. In conclusion, our data suggest that defective autophagy in SMCs enhances atherosclerotic changes with outward arterial remodeling.

Keywords: Aneurysm; atherosclerosis; autophagy; cell death; senescence; smooth muscle cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism
  • Aorta / pathology
  • Apolipoproteins E / genetics
  • Atherosclerosis / genetics*
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Autophagy / genetics*
  • Autophagy-Related Protein 7 / deficiency
  • Autophagy-Related Protein 7 / genetics*
  • Cell Death / genetics
  • Cells, Cultured
  • Disease Models, Animal
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth, Vascular / pathology
  • Muscle, Smooth, Vascular / physiology*
  • Plaque, Atherosclerotic / genetics
  • Plaque, Atherosclerotic / metabolism
  • Plaque, Atherosclerotic / pathology
  • Vascular Remodeling / genetics

Substances

  • Apolipoproteins E
  • Atg7 protein, mouse
  • Autophagy-Related Protein 7

Grants and funding

This work was supported by grants from the Ministry of Education, Sports and Culture of Japan (to H.W. [JSPS KAKENHI; grant numbers JP 16H01205 and JP 26293220] and (to T.M. [JSPS KAKENHI grant numbers JP 24790782 and JP 16K01833]), and Japan Agency for Medical Research and Development (AMED) (toY.F.[JP18gm0610005]), and the Takeda Science Foundation (to T.M.), Research Fund of Mitsukoshi Health and Welfare foundation 2016 (to T.M.), the Juntendo University Young Investigator Joint Project Award 2015 (grant no.(2710) (to Y.O.), Suzuken Memorial Foundation 2015 (to Y.O.), and MSD Life Science Foundation 2017 (to Y.O.), Japan Foundation for Applied Enzymology (to T.M.), MSD, Ono Pharmaceutical Company, Mitsubishi Tanabe Pharma Corporation, Kowa Company Ltd., and Boehringer Ingelheim Pharmaceuticals, Inc. (to H. W.)