https://orcid.org/0000-0002-3174-5684
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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.
Abbreviations
| ACTA2 | = | actin, alpha 2, smooth muscle, aorta |
| APOE | = | apolipoprotein E |
| BBC3 | = | BCL2 binding component 3 |
| BP | = | blood pressure |
| BrdU | = | bromodeoxyuridine |
| CASP3 | = | caspase 3 |
| CCL2 | = | chemokine (C-C motif) ligand 2 |
| ELISA | = | enzyme-linked immunosorbent assay |
| FBS | = | fetal bovine serum |
| GLB1 | = | galactosidase, beta 1 |
| H2AFX | = | H2A histone family, member X |
| 7-KC | = | 7-ketocholesterol |
| LGALS3 | = | lectin, galactose binding, soluble 3 |
| MAP1LC3B | = | microtubule-associated protein 1 light chain 3 beta |
| MMP9 | = | matrix metallopeptidase 9 |
| NAC | = | N-acetylcysteine |
| PCNA | = | proliferating cell nuclear antigen |
| SMCs | = | smooth muscle cells |
| SQSTM1 | = | sequestosome 1 |
| TEM | = | transmission electron microscopy |
| TAGLN | = | transgelin |
| TRP53/TP53 | = | transformation related protein 53 |
Acknowledgments
We thank Dr. Masaaki Komatsu (Niigata University Graduate School of Medical and Dental Sciences) for providing Atg7f/f mice, and Ms. N. Daimaru, Ms. E. Magoshi, Ms. H. Hibino, and Ms. S. Ishikawa for their excellent technical assistance.
Disclosure statement
No potential conflict of interest was reported by the authors.
Supplementary material
Supplementary data for this article can be accessed here.
