蛋白聚糖 4 在不改变动脉粥样硬化病变形成的情况下调节巨噬细胞功能的小鼠骨髓特异性缺失模型。
Proteoglycan 4 regulates macrophage function without altering atherosclerotic lesion formation in a murine bone marrow-specific deletion model.
机构信息
Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), The Netherlands.
Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), The Netherlands.
出版信息
Atherosclerosis. 2018 Jul;274:120-127. doi: 10.1016/j.atherosclerosis.2018.05.008. Epub 2018 May 5.
BACKGROUND AND AIMS
Proteoglycan 4 (Prg4) has a high structural similarity with the established atherosclerosis-modulating proteoglycan versican, but its role in atherogenesis is still unknown. Therefore, the impact of Prg4 deficiency on macrophage function in vitro and atherosclerosis susceptibility in vivo was investigated.
METHODS
The presence and localization of Prg4 was studied in atherosclerotic lesions. Furthermore, the effect of Prg4 deficiency on macrophage foam cell formation, cholesterol efflux and lipopolysaccharide (LPS) response was determined. Finally, susceptibility for atherosclerotic lesion formation was investigated in bone marrow-specific Prg4 knockout (KO) mice.
RESULTS
Prg4 mRNA expression was induced 91-fold (p<0.001) in murine initial atherosclerotic lesions and Prg4 protein co-localized with human lesional macrophages. Murine Prg4 KO macrophages showed increased foam cell formation (+2.1-fold, p<0.01). In parallel, the expression of the cholesterol efflux genes ATP-binding cassette transporter A1 and scavenger receptor type B1 was lower (-35%, p<0.05;-40%, p<0.05) in Prg4 KO macrophages. This translated into an impaired cholesterol efflux to high-density lipoprotein (-13%, p<0.001) and apolipoprotein A1 (-8%, p<0.05). Furthermore, Prg4 KO macrophages showed an impaired LPS-induced rise in TNFα secretion as compared to wild-type controls (-31%, p<0.001), indicating a reduced inflammatory response. Combined, these pro- and anti-atherogenic effects did not translate into a significant difference in atherosclerotic lesion formation upon bone marrow-specific deletion of Prg4 in low-density lipoprotein receptor KO mice.
CONCLUSIONS
Prg4 is present in macrophages in both murine and human atherosclerotic lesions and critically influences macrophage function, but deletion of Prg4 in bone marrow-derived cells does not affect atherosclerotic lesion development.
背景与目的
蛋白聚糖 4（Prg4）与已确立的动脉粥样硬化调节蛋白聚糖 versican 具有高度的结构相似性，但它在动脉粥样硬化形成中的作用尚不清楚。因此，本研究旨在研究 Prg4 缺乏对体外巨噬细胞功能和体内动脉粥样硬化易感性的影响。
方法
研究了动脉粥样硬化病变中 Prg4 的存在和定位。此外，还确定了 Prg4 缺乏对巨噬细胞泡沫细胞形成、胆固醇流出和脂多糖（LPS）反应的影响。最后，在骨髓特异性 Prg4 敲除（KO）小鼠中研究了动脉粥样硬化病变形成的易感性。
结果
Prg4 mRNA 表达在小鼠初始动脉粥样硬化病变中诱导了 91 倍（p<0.001），Prg4 蛋白与人类病变巨噬细胞共定位。Prg4 KO 巨噬细胞的泡沫细胞形成增加（+2.1 倍，p<0.01）。平行地，胆固醇流出基因 ATP 结合盒转运体 A1 和清道夫受体 B1 的表达在 Prg4 KO 巨噬细胞中降低（-35%，p<0.05；-40%，p<0.05）。这转化为胆固醇向高密度脂蛋白的流出减少（-13%，p<0.001）和载脂蛋白 A1 的流出减少（-8%，p<0.05）。此外，与野生型对照相比，Prg4 KO 巨噬细胞的 LPS 诱导 TNFα 分泌升高受到抑制（-31%，p<0.001），表明炎症反应减弱。综合来看，这些促动脉粥样硬化和抗动脉粥样硬化作用在 LDL 受体 KO 小鼠骨髓特异性缺失 Prg4 时并未导致动脉粥样硬化病变形成的显著差异。
结论
Prg4 存在于鼠类和人类动脉粥样硬化病变中的巨噬细胞中，并严重影响巨噬细胞功能，但骨髓源性细胞中 Prg4 的缺失不影响动脉粥样硬化病变的发展。
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