Defective autophagy in vascular smooth muscle cells enhances atherosclerotic plaque instability

Atsushi Masuyama; Tomoya Mita; Kosuke Azuma; Yusuke Osonoi; Kenichi Nakajima; Hiromasa Goto; Yuya Nishida; Takeshi Miyatsuka; Masako Mitsumata; Hirotaka Watada

doi:10.1016/j.bbrc.2018.09.192

Defective autophagy in vascular smooth muscle cells enhances atherosclerotic plaque instability

Biochem Biophys Res Commun. 2018 Nov 10;505(4):1141-1147. doi: 10.1016/j.bbrc.2018.09.192. Epub 2018 Oct 11.

Authors

Affiliations

¹ Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
² Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan; Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan; Center for Identification of Diabetic Therapeutic Targets, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. Electronic address: [email protected].
³ Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan; Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
⁴ Division of Cardiology, Department of Medicine, Yamanashi Kosei Hospital, 860 Oshiai, Yamanashi City, Yamanashi, 405-0033, Japan.
⁵ Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan; Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan; Center for Identification of Diabetic Therapeutic Targets, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

PMID: 30318118
DOI: 10.1016/j.bbrc.2018.09.192

Abstract

Autophagy is considered as an evolutionarily conserved cellular catabolic process. Defective autophagy has been implicated in various human diseases, including cardiovascular diseases. Recently, we and others demonstrated that defective autophagy in vascular smooth muscle cells (SMCs) promotes the progression of atherosclerosis. In this study, we investigated the role of autophagy in SMCs on plaque instability in vivo. We generated mice with a defect atg7in which is an essential gene for autophagy, in SMCs by crossing Atg7^f/f mice with transgelin (Tagln) Cre^+/0 mice (Atg7cKO). Then, Atg7cKO and apolipoprotein E (apoe)-deficient (apoeKO) mice were crossed to generate Atg7cKO:apoeKO mice. To generate a mouse model of plaque instability, we conducted to form a tandem stenosis in the carotid artery of Atg7cKO:apoeKO mice and their controls (apoeKO mice) at the age of 10 weeks. At 5 weeks after surgery, the percentage of cross-sectional stenosis area in the operated common carotid artery of Atg7cKO:apoeKO mice was significantly higher than that in apoeKO mice. In addition, thrombus, which was not observed in apoeKO mice, was frequently found in Atg7cKO:apoeKO mice. Furthermore, the number of Berlin blue staining-positive areas, which indicated intraplaque hemorrhage, was significantly higher in Atg7cKO:apoeKO mice than in control apoeKO mice. Taken together, our data suggest that defective autophagy in SMCs enhances plaque instability and the risk of plaque rupture.

Keywords: Atheroma; Autophagy; Plaque instability; Smooth muscle cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apolipoproteins E / deficiency
Apolipoproteins E / genetics
Autophagy*
Disease Models, Animal
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocytes, Smooth Muscle / metabolism*
Myocytes, Smooth Muscle / pathology
Plaque, Atherosclerotic / metabolism*
Plaque, Atherosclerotic / pathology
Spinal Stenosis / metabolism
Spinal Stenosis / pathology
Spinal Stenosis / surgery

Substances

Apolipoproteins E