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.
Department of Pathology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Biochim Biophys Acta Mol Basis Dis. 2022 Sep 1;1868(9):166450. doi: 10.1016/j.bbadis.2022.166450. Epub 2022 May 20.
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.
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.
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.
Our results highlight the importance of BMAL1 as a major regulator in VSMCs phenotypic switch towards fibroblast-like cells which stabilize an atherosclerotic plaque.
缺血性心脏病和缺血性脑卒中与生物钟和不稳定的动脉粥样硬化斑块密切相关。血管平滑肌细胞（VSMCs）可以通过表型转换稳定或破坏动脉粥样硬化病变。BMAL1 不仅是生物钟不可或缺的核心组成部分，也是动脉粥样硬化和 VSMCs 增殖的重要调节剂。然而，BMAL1 在 VSMCs 表型转换和动脉粥样硬化斑块稳定性中的调控机制知之甚少。
我们综合分析了人类斑块的组织学特征、VSMC 特异性 Bmal1 小鼠的体内实验、体外实验以及人类斑块的公共数据集的基因集富集分析（GSEA），以探讨 BMAL1 在 VSMCs 表型转换和斑块稳定性中的作用。
与不稳定的人类斑块相比，稳定斑块中 BMAL1 表达更高，同时 YAP1 和成纤维细胞标志物 FSP1 也升高，且与 BMAL1 呈正相关。在 Methyl-β-cyclodextrin-cholesterol、氧化型低密度脂蛋白和血小板衍生生长因子-BB 的刺激下，VSMCs 发生表型转换，BMAL1、YAP1 和 FSP1 表达上调。此外，BMAL1 过表达通过转录上调 YAP1 的表达促进 VSMCs 向成纤维样细胞的表型转换。BMAL1 或 YAP1 的敲低抑制 VSMCs 的表型转换，下调 FSP1 的表达。此外，VSMC 特异性 Bmal1 小鼠的 VSMCs 中 YAP1 和 FSP1 水平较低，斑块较脆弱，胶原含量较少。此外，BMAL1 抑制 VSMCs 的迁移。公共数据集的 GSEA 结果与我们的实验室结果一致。
我们的研究结果强调了 BMAL1 作为 VSMCs 向成纤维样细胞表型转换的主要调节因子的重要性，这种表型转换稳定了动脉粥样硬化斑块。
