ApoE Receptor-2 R952Q Variant in Macrophages Elevates Soluble LRP1 to Potentiate Hyperlipidemia and Accelerate Atherosclerosis in Mice.

IF 7.4 1区 医学 Q1 HEMATOLOGY Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2024-11-07 DOI:10.1161/ATVBAHA.124.321748
Vanessa Turkson, April Haller, Anja Jaeschke, David Y Hui
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Abstract

Background: apoER2 (apolipoprotein E receptor-2) is a transmembrane receptor in the low-density lipoprotein receptor (LDLR) family with unique tissue expression. A single-nucleotide polymorphism that encodes the R952Q sequence variant has been associated with elevated plasma cholesterol levels and increased myocardial infarction risk in humans. The objective of this study was to delineate the mechanism underlying the association between the apoER2 R952Q variant and increased atherosclerosis risk.

Methods: An apoER2 R952Q mouse model was generated using a CRISPR/Cas9 strategy, intercrossed with LDLR knockout mice, followed by feeding a Western-type high-fat high-cholesterol diet for 16 weeks. Atherosclerosis was investigated by immunohistology. Plasma lipids and lipid distributions among the various lipoprotein classes were analyzed by colorimetric assay. Tissue-specific effects of the R952Q sequence variant on atherosclerosis were analyzed by bone marrow transplant studies. sLRP1 (soluble low-density lipoprotein receptor-related protein 1) was measured in plasma and conditioned media from bone marrow-derived macrophages by ELISA and GST-RAP (glutathione S-transferase-receptor-associated protein) pull-down, respectively. P38 MAPK (mitogen-activated protein kinase) phosphorylation in VLDL (very-low-density lipoprotein)-treated macrophages was determined by Western blot analysis.

Results: Consistent with observations in humans with this sequence variant, the apoER2 R952Q mutation exacerbated diet-induced hypercholesterolemia, via impediment of plasma triglyceride-rich lipoprotein clearance, to accelerate atherosclerosis in Western diet-fed LDLR knockout mice. Reciprocal bone marrow transplant experiments revealed that the apoER2 R952Q mutation in bone marrow-derived cells instead of non-bone marrow-derived cells was responsible for the increase in hypercholesterolemia and atherosclerosis. Additional data showed that the apoER2 R952Q mutation in macrophages promotes VLDL-induced LRP1 (low-density lipoprotein receptor-related protein 1) shedding in a p38 MAPK-dependent manner.

Conclusions: The apoER2 R952Q mouse model recapitulates characteristics observed in human disease. The underlying mechanism is that the apoER2 R952Q mutation in macrophages exacerbates VLDL-stimulated sLRP1 production in a p38 MAPK-dependent manner, resulting in its competition with cell surface LRP1 to impede triglyceride-rich lipoprotein clearance, thereby resulting in increased hypercholesterolemia and accelerated atherosclerosis.

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巨噬细胞中的载脂蛋白E受体-2 R952Q变异可使可溶性LRP1升高,从而加剧小鼠的高脂血症并加速动脉粥样硬化。
背景:载脂蛋白 E 受体-2(apolipoprotein E receptor-2)是低密度脂蛋白受体(LDLR)家族中的一种跨膜受体,具有独特的组织表达。编码 R952Q 序列变异的单核苷酸多态性与人体血浆胆固醇水平升高和心肌梗死风险增加有关。本研究的目的是阐明apoER2 R952Q变异与动脉粥样硬化风险增加之间的关联机制:方法:采用 CRISPR/Cas9 策略生成载脂蛋白 E2 R952Q 小鼠模型,与 LDLR 基因敲除小鼠杂交,然后喂食西式高脂高胆固醇饮食 16 周。动脉粥样硬化通过免疫组织学进行研究。用比色法分析血浆脂质和脂质在不同脂蛋白类别中的分布。通过 ELISA 和 GST-RAP(谷胱甘肽 S-转移酶-受体相关蛋白)牵引法分别测量了血浆和骨髓巨噬细胞条件培养基中的 sLRP1(可溶性低密度脂蛋白受体相关蛋白 1)。通过 Western 印迹分析测定了经 VLDL(极低密度脂蛋白)处理的巨噬细胞中的 P38 MAPK(丝裂原活化蛋白激酶)磷酸化:结果:与在人类中观察到的该序列变异一致,apoER2 R952Q突变通过阻碍血浆中富含甘油三酯的脂蛋白清除,加剧了饮食诱导的高胆固醇血症,加速了西方饮食喂养的LDLR基因敲除小鼠的动脉粥样硬化。互补骨髓移植实验表明,骨髓源性细胞而非非骨髓源性细胞中的载脂蛋白原2 R952Q突变是导致高胆固醇血症和动脉粥样硬化增加的原因。其他数据显示,巨噬细胞中的载脂蛋白ER2 R952Q突变以p38 MAPK依赖性方式促进VLDL诱导的LRP1(低密度脂蛋白受体相关蛋白1)脱落:结论:载脂蛋白ER2 R952Q小鼠模型再现了人类疾病的特征。其基本机制是巨噬细胞中的 apoER2 R952Q 突变以 p38 MAPK 依赖性方式加剧了 VLDL 刺激的 sLRP1 的产生,导致其与细胞表面的 LRP1 竞争,阻碍富含甘油三酯的脂蛋白的清除,从而导致高胆固醇血症的增加和动脉粥样硬化的加速。
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来源期刊
CiteScore
15.60
自引率
2.30%
发文量
337
审稿时长
2-4 weeks
期刊介绍: The journal "Arteriosclerosis, Thrombosis, and Vascular Biology" (ATVB) is a scientific publication that focuses on the fields of vascular biology, atherosclerosis, and thrombosis. It is a peer-reviewed journal that publishes original research articles, reviews, and other scholarly content related to these areas. The journal is published by the American Heart Association (AHA) and the American Stroke Association (ASA). The journal was published bi-monthly until January 1992, after which it transitioned to a monthly publication schedule. The journal is aimed at a professional audience, including academic cardiologists, vascular biologists, physiologists, pharmacologists and hematologists.
期刊最新文献
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