Echinatin maintains glutathione homeostasis in vascular smooth muscle cells to protect against matrix remodeling and arterial stiffening

动脉硬化 GCLC公司 平衡 下调和上调 弹性蛋白 GCLM公司 血管平滑肌 细胞生物学 谷胱甘肽 KLF2 化学 内分泌学 内科学 药理学 平滑肌 医学 生物 病理 血压 生物化学 基因
作者
Jianrui Zhang,Sian Xie,Jin Wang,Jiayu Liu,Yueqi Liu,Shuang Zhou,Xixi Li,Lili Han,Wei Pang,Weijuan Yao,Yi Fu,Wei Kong,Min Ye,Jing Zhou
出处
期刊:Matrix Biology [Elsevier BV]
卷期号:119: 1-18 被引量:5
标识
DOI:10.1016/j.matbio.2023.03.007
摘要

Decreased vascular compliance of the large arteries as indicated by increased pulse wave velocity is shown to be associated with atherosclerosis and the related cardiovascular events. The positive correlation between arterial stiffening and disease progression derives a hypothesis that softening the arterial wall may protect against atherosclerosis, despite that the mechanisms controlling the cellular pathological changes in disease progression remain unknown. Here, we established a mechanical-property-based screening to look for compounds alleviating the arterial wall stiffness through their actions on the interaction between vascular smooth muscle cells (VSMCs) and the wall extracellular matrix (ECM). We found that echinatin, a chalcone preferentially accumulated in roots and rhizomes of licorice (Glycyrrhiza inflata), reduced the stiffness of ECM surrounding cultured VSMCs. We examined the potential beneficial effects of echinatin on mitigating arterial stiffening and atherosclerosis, and explored the mechanistic basis by which the compound exert the effects. Administration of echinatin in mice fed on an adenine diet and in hyperlipidemia mice subjected to 5/6 nephrectomy mitigated arterial stiffening and atherosclerosis. Mechanistic insights were gained from the RNA-sequencing results showing that echinatin upregulated the expression of glutamate cysteine ligases (GCLs), both the catalytic (GCLC) and modulatory (GCLM) subunits. Further study indicated that upregulation of GCLC/GCLM in VSMCs by echinatin maintains the homeostasis of glutathione (GSH) metabolism; adequate availability of GSH is critical for counteracting arterial stiffening. As a consequence of regulating the GSH synthesis, echinatin inhibits ferroptosis and matrix remodeling that being considered two contributors of arterial stiffening and atherosclerosis. These data demonstrate a pivotal role of GSH dysregulation in damaging the proper VSMC-ECM interaction and uncover a beneficial activity of echinatin in preventing vascular diseases.
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