S1PR2 Mediates Smooth Muscle Cell Proliferation and Endothelial Cell Permeability via Akt/mTOR and RhoA/ROCK1 in Atherosclerosis

IF 3.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jie Ouyang, Haijiao Long, Shuhua Chen, Hong Xiang, Zhihao Shu, Xuewen Wang, Jing Zhang, Huiqin Liu, Baiyi Tang, Jie Xiao, Quanjun Liu, Zishun Zhan, Ruifang Chen, Hongwei Lu
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Abstract

Atherosclerosis is a complex disease involving a series of interrelated events, among which endothelial cell dysfunction and vascular smooth muscle cell proliferation play pivotal roles in the early formation of atherosclerotic plaques. Sphingosine 1-phosphate, a product of sphingomyelin metabolism, serves as a signaling molecule implicated in the pathogenesis of atherosclerosis and other conditions by binding to sphingosine 1-phosphate receptors (S1PRs). However, the precise mechanism by which S1PRs influence atherosclerosis remains incompletely understood. Here, we identified a dual role for S1PR2 in vascular cells treated with oxidized-low-density lipoprotein. In smooth muscle cells, decreased S1PR2 upregulated PCNA expression by activating Akt/mTOR, leading to abnormal cell proliferation. Conversely, in endothelial cells, elevated S1PR2 expression reduced VE-cadherin expression by activating the RhoA/ROCK1 pathway, increasing endothelial permeability. In an apolipoprotein E-deficient mouse model, S1PR2 agonist treatment reduced the abnormal proliferation of aortic smooth muscle cells, while S1PR2 antagonist treatment alleviated barrier function damage in aortic endothelial cells. However, both S1PR2 agonist and antagonist treatments showed limited efficacy on aortic plaques due to their opposing effects on endothelial cells and smooth muscle cells. Thus, therapies targeting specific cell types hold significant promise, and S1PR2 may be a potential target for the prevention and treatment of atherosclerosis.

Abstract Image

S1PR2通过Akt/mTOR和RhoA/ROCK1介导动脉粥样硬化中平滑肌细胞增殖和内皮细胞通透性
动脉粥样硬化是一种复杂的疾病,涉及一系列相互关联的事件,其中内皮细胞功能障碍和血管平滑肌细胞增殖在动脉粥样硬化斑块的早期形成中起关键作用。鞘氨醇1-磷酸是鞘磷脂代谢的产物,是一种信号分子,通过与鞘氨醇1-磷酸受体(S1PRs)结合,参与动脉粥样硬化等疾病的发病。然而,S1PRs影响动脉粥样硬化的确切机制尚不完全清楚。在这里,我们确定了S1PR2在氧化低密度脂蛋白处理的血管细胞中的双重作用。在平滑肌细胞中,S1PR2的降低通过激活Akt/mTOR上调PCNA的表达,导致细胞增殖异常。相反,在内皮细胞中,S1PR2表达升高通过激活RhoA/ROCK1通路降低VE-cadherin表达,增加内皮通透性。在载脂蛋白e缺陷小鼠模型中,S1PR2激动剂治疗可减少主动脉平滑肌细胞的异常增殖,而S1PR2拮抗剂治疗可减轻主动脉内皮细胞屏障功能损伤。然而,S1PR2激动剂和拮抗剂治疗对主动脉斑块的疗效有限,因为它们对内皮细胞和平滑肌细胞的作用相反。因此,针对特定细胞类型的治疗具有重要的前景,S1PR2可能是预防和治疗动脉粥样硬化的潜在靶点。
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来源期刊
CiteScore
5.80
自引率
2.80%
发文量
277
审稿时长
6-12 weeks
期刊介绍: The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.
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