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
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DOI：
10.1016/j.bbadis.2022.166450
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发表时间：
2022-05-25
影响因子：
6.2
通讯作者：
Guo，Da-qiao
中科院分区：
文献类型：
--
作者：
Shen，Yang;Xu，Li-rong;Guo，Da-qiao
BackgroundIschemic 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.MethodsWe integrated histological analysis of human plaques, in vivo experiments of VSMC-specificBmal1−/−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.FindingsComparing 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 ofYAP1.BMAL1orYAP1knock-down inhibited VSMCs phonotypic switch and downregulated FSP1. Furthermore, VSMC-specificBmal1−/−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.InterpretationOur results highlight the importance of BMAL1 as a major regulator in VSMCs phenotypic switch towards fibroblast-like cells which stabilize an atherosclerotic plaque.
