暨南大学闫道广课题组《Circulation Research》发表血管损伤新发现

　　

日前，暨南大学闫道广教授课题组取得了血管损伤与动脉粥样硬化形成的机制性发现。这一研究成果公布在心血管生物学与外周血管疾病国际顶级期刊《Circulation Research》（IF：11.55）上。

巨噬细胞凋亡是动脉粥样硬化形成和发展的中心事件。氧化低密度脂蛋白及其中负载的氧化固醇诱导细胞凋亡是否有相关的受体蛋白分子参与的问题仍有待揭示。

最新研究首次发现，作为细胞内氧化固醇的受体，ORP4L建立的 Ca2+信号通路对维持巨噬细胞的生存至关重要。血管微环境中过量蓄积的氧化固醇/氧化低密度脂蛋白通过结合ORP4L，抑制ORP4L的正常功能，诱导巨噬细胞凋亡。

这项研究提供了一个氧化固醇/氧化低密度脂蛋白细胞毒性的机制模型。通过基因敲除小鼠模型，研究人员证明ORP4L是影响动脉粥样硬化发生发展的关键蛋白。他们从分子、细胞、组织和整体动物水平多层次验证了该理论，为动脉粥样硬化过程中巨噬细胞的凋亡提供机制解释，加深人们对血管损伤及动脉粥样硬化发生、发展的理解。ORP4L可能成为干预动脉粥样硬化疾病进程的重要靶标。

暨南大学博士生钟文彬、本科生/硕士生潘国平、硕士生汪林为论文共同第一作者，教授闫道广为论文通讯作者。研究得到科技部重大基础研究计划（973项目）、国家自然科学基金委面上/重大研究计划项目、暨南大学科研培育与创新基金重点重大项目培育项目等的支持。

Model outlining the functions of ORP4L in macrophages

原文摘要：

ORP4L Facilitates Macrophage Survival via G-Protein–Coupled Signaling

Rationale: Macrophage survival within the arterial wall is a central factor contributing to atherogenesis. Oxysterols, major components of oxidized low-density lipoprotein, exert cytotoxic effects on macrophages.

Objective: To determine whether oxysterol-binding protein–related protein 4 L (ORP4L), an oxysterol-binding protein, affects macrophage survival and the pathogenesis of atherosclerosis.

Methods and Results: By hiring cell biological approaches and ORP4L−/− mice, we show that ORP4L coexpresses with and forms a complex with Gαq/11 and phospholipase C (PLC)-β3 in macrophages. ORP4L facilitates G-protein–coupled ligand-induced PLCβ3 activation, IP3 production, and Ca2+ release from the endoplasmic reticulum. Through this mechanism, ORP4L sustains antiapoptotic Bcl-XL expression through Ca2+-mediated c-AMP responsive element binding protein transcriptional regulation and thus protects macrophages from apoptosis. Excessive stimulation with the oxysterol 25-hydroxycholesterol disassembles the ORP4L/Gαq/11/PLCβ3 complexes, resulting in reduced PLCβ3 activity, IP3 production, and Ca2+ release, as well as decreased Bcl-XL expression and increased apoptosis. Overexpression of ORP4L counteracts these oxysterol-induced defects. Mice lacking ORP4L exhibit increased apoptosis of macrophages in atherosclerotic lesions and a reduced lesion size.

Conclusions: ORP4L is crucial for macrophage survival. It counteracts the cytotoxicity of oxysterols/oxidized low-density lipoprotein to protect macrophage from apoptosis, thus playing an important role in the development of atherosclerosis.