2. Academic Validation
  3. BMAL1 modulates smooth muscle cells phenotypic switch towards fibroblast-like cells and stabilizes atherosclerotic plaques by upregulating YAP1

BMAL1 modulates smooth muscle cells phenotypic switch towards fibroblast-like cells and stabilizes atherosclerotic plaques by upregulating YAP1

  • Biochim Biophys Acta Mol Basis Dis. 2022 Sep 1;1868(9):166450. doi: 10.1016/j.bbadis.2022.166450.
Yang Shen 1,  Li-Rong Xu 2,  Dong Yan 1,  Min Zhou 1,  Tong-Lei Han 1,  Chao Lu 3,  Xiao Tang 1,  Chang-Po Lin 4,  Rui-Zhe Qian 5,  Da-Qiao Guo 6
Affiliations

Affiliations

  • 1 Department of Vascular Surgery, Institute of Vascular Surgery, National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai 200032, China.
  • 2 Department of Pathology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 3 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Rd., Shanghai 200032, China.
  • 4 Department of Vascular Surgery, Institute of Vascular Surgery, National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai 200032, China. Electronic address: [email protected].
  • 5 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Rd., Shanghai 200032, China. Electronic address: [email protected].
  • 6 Department of Vascular Surgery, Institute of Vascular Surgery, National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai 200032, China. Electronic address: [email protected].
PMID: 35598770 DOI: 10.1016/j.bbadis.2022.166450
Abstract

Background: Ischemic heart diseases and ischemic stroke are closely related to circadian clock and unstable atherosclerotic plaques. Vascular smooth muscle cells (VSMCs) can stabilize or destabilize an atherosclerotic lesion through phenotypic switch. BMAL1 is not only an indispensable core component in circadian clock but also an important regulator in atherosclerosis and VSMCs proliferation. However, little is known about the modulation mechanisms of BMAL1 in VSMCs phenotypic switch and atherosclerotic plaque stability.

Methods: We integrated histological analysis of human plaques, in vivo experiments of VSMC-specific Bmal1-/- mice, in vitro experiments, and gene set enrichment analysis (GSEA) of public datasets of human plaques to explore the function of BMAL1 in VSMCs phonotypic switch and plaque stability.

Findings: Comparing to human unstable plaques, BMAL1 was higher in stable plaques, accompanied by elevated YAP1 and fibroblast maker FSP1 which were positively correlated with BMAL1. In response to Methyl-β-cyclodextrin-cholesterol, oxidized-low-density-lipoprotein and platelet-derived-growth-factor-BB, VSMCs embarked on phenotypic switch and upregulated BMAL, YAP1 and FSP1. Besides, BMAL1 overexpression promoted VSMCs phonotypic switch towards fibroblast-like cells by transcriptionally upregulating the expression of YAP1. BMAL1 or YAP1 knock-down inhibited VSMCs phonotypic switch and downregulated FSP1. Furthermore, VSMC-specific Bmal1-/- mice exhibited VSMCs with lower YAP1 and FSP1 levels, and more vulnerable plaques with less collagen content. In addition, BMAL1 suppressed the migration of VSMCs. The GSEA results of public datasets were consistent with our laboratory findings.

Interpretation: Our results highlight the importance of BMAL1 as a major regulator in VSMCs phenotypic switch towards fibroblast-like cells which stabilize an atherosclerotic plaque.

Keywords

BMAL1; Phenotypic switch; Plaque stability; Vascular smooth muscle cell; YAP1.

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