Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, 3 Blackfan Circle, CLSB, Floor 17, Boston, MA 02115, USA.
Eur Heart J. 2013 Feb;34(8):615-24. doi: 10.1093/eurheartj/ehs271. Epub 2012 Aug 26.
Activation of vascular endothelial cells (ECs) contributes importantly to inflammation and atherogenesis. We previously reported that apolipoprotein CIII (apoCIII), found abundantly on circulating triglyceride-rich lipoproteins, enhances adhesion of human monocytes to ECs in vitro. Statins may exert lipid-independent anti-inflammatory effects. The present study examined whether statins suppress apoCIII-induced EC activation in vitro and in vivo.
Physiologically relevant concentrations of purified human apoCIII enhanced attachment of the monocyte-like cell line THP-1 to human saphenous vein ECs (HSVECs) or human coronary artery ECs (HCAECs) under both static and laminar shear stress conditions. This process mainly depends on vascular cell adhesion molecule-1 (VCAM-1), as a blocking VCAM-1 antibody abolished apoCIII-induced monocyte adhesion. ApoCIII significantly increased VCAM-1 expression in HSVECs and HCAECs. Pre-treatment with statins suppressed apoCIII-induced VCAM-1 expression and monocyte adhesion, with two lipophilic statins (pitavastatin and atorvastatin) exhibiting inhibitory effects at lower concentration than those of hydrophilic pravastatin. Nuclear factor κB (NF-κB) mediated apoCIII-induced VCAM-1 expression, as demonstrated via loss-of-function experiments, and pitavastatin treatment suppressed NF-κB activation. Furthermore, in the aorta of hypercholesterolaemic Ldlr(-/-) mice, pitavastatin administration in vivo suppressed VCAM-1 mRNA and protein, induced by apoCIII bolus injection. Similarly, in a subcutaneous dorsal air pouch mouse model of leucocyte recruitment, apoCIII injection induced F4/80+ monocyte and macrophage accumulation, whereas pitavastatin administration reduced this effect.
These findings further establish the direct role of apoCIII in atherogenesis and suggest that anti-inflammatory effects of statins could improve vascular disease in the population with elevated plasma apoCIII.
血管内皮细胞（EC）的激活对炎症和动脉粥样硬化形成有重要作用。我们之前报道过，载脂蛋白 CIII（apoCIII）在循环富含甘油三酯的脂蛋白中大量存在，可增强人单核细胞在体外与 EC 的黏附。他汀类药物可能具有脂质非依赖性的抗炎作用。本研究检测了他汀类药物是否能抑制体外和体内 apoCIII 诱导的 EC 激活。
生理相关浓度的纯化人 apoCIII 在静态和层流剪切应力条件下增强单核细胞样细胞系 THP-1 与人体大隐静脉 EC（HSVEC）或人冠状动脉 EC（HCAEC）的黏附。这个过程主要依赖于血管细胞黏附分子-1（VCAM-1），因为阻断 VCAM-1 的抗体消除了 apoCIII 诱导的单核细胞黏附。apoCIII 显著增加了 HSVEC 和 HCAEC 中的 VCAM-1 表达。他汀类药物预处理抑制了 apoCIII 诱导的 VCAM-1 表达和单核细胞黏附，两种亲脂性他汀类药物（匹伐他汀和阿托伐他汀）的抑制作用浓度低于亲水性普伐他汀。核因子 κB（NF-κB）介导 apoCIII 诱导的 VCAM-1 表达，通过失活实验证明，匹伐他汀处理抑制 NF-κB 激活。此外，在高胆固醇血症 LDLr（-/-）小鼠的主动脉中，体内给予匹伐他汀抑制 apoCIII 弹丸注射诱导的 VCAM-1 mRNA 和蛋白。同样，在白细胞募集的皮下背部气囊中鼠模型中，apoCIII 注射诱导 F4/80+单核细胞和巨噬细胞积聚，而匹伐他汀给药减少了这种效应。
这些发现进一步证实了 apoCIII 在动脉粥样硬化形成中的直接作用，并表明他汀类药物的抗炎作用可能改善血浆 apoCIII 升高人群的血管疾病。
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