Sox9 mediates autophagy-dependent vascular smooth muscle cell phenotypic modulation and transplant arteriosclerosis

Qihong Yu; Jin-Xin Liu; Xichuan Zheng; Xueke Yan; Peng Zhao; Chuanzheng Yin; Wei Li; Zifang Song

doi:10.1016/j.isci.2022.105161

Sox9 mediates autophagy-dependent vascular smooth muscle cell phenotypic modulation and transplant arteriosclerosis

iScience. 2022 Sep 21;25(10):105161. doi: 10.1016/j.isci.2022.105161. eCollection 2022 Oct 21.

Authors

Qihong Yu^{1

2}, Jin-Xin Liu³, Xichuan Zheng⁴, Xueke Yan⁴, Peng Zhao⁴, Chuanzheng Yin⁴, Wei Li⁵, Zifang Song⁴

Affiliations

¹ Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
² Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan 430030, China.
³ Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
⁴ Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
⁵ Departments of Gerontology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

Abstract

Vascular smooth muscle cell (vSMC) phenotypic modulation is a dynamic pathogenesis process implicated in neointimal formation and transplant arteriosclerosis (TA). Transcription factor Sox9 functions to establish cell type and wound healing, but little is known about its transcriptional regulation in vSMCs and its roles in the development of TA. Here, we found an increased Sox9 expression in aortic allografts and in HMGB1-treated vSMCs in vitro, accompanied by the downregulation of vSMC markers. Notably, vSMC-specific Sox9 knockdown in aortic allografts attenuated neointimal formation through preventing vSMC phenotypic modulation following transplantation. We further indicated that HMGB1 induced Sox9 expression and vSMC phenotypic modulation through activating autophagy to degrade p27^Kip1. Mechanistically, p27^Kip1 bound to the Sox9 promoter in vSMCs together with p130/E2F4 complex, by which it restrained Sox9 transcriptional expression. These findings uncover a fundamental role of Sox9 in mediating autophagy-dependent vSMC phenotypic modulation and TA, offering a therapeutic approach for vascular pathologies.

Keywords: Cardiovascular medicine; Molecular biology; Omics.