Electronegative low-density lipoprotein increases C-reactive protein expression in vascular endothelial cells through the LOX-1 receptor.
Electronegative low-density lipoprotein increases C-reactive protein expression in vascular endothelial cells through the LOX-1 receptor.
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DOI：
10.1371/journal.pone.0070533
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lu J
中科院分区：
文献类型：
--
作者：
Chu CS;Wang YC;Lu LS;Walton B;Yilmaz HR;Huang RY;Sawamura T;Dixon RA;Lai WT;Chen CH;Lu J
血浆C反应蛋白（CRP）水平升高与急性冠状动脉综合征的发生和严重程度相关。我们研究了CRP是否可以产生在血管内皮细胞（EC）暴露后的低密度脂蛋白（LDL），L5，这是动脉粥样硬化的EC的最负性的亚组分。由于L5和CRP都是凝集素样氧化LDL受体-1（LOX-1）的配体，因此我们也研究了LOX-1的作用。从无症状高胆固醇血症（LDL胆固醇[LDL-C]水平，154.6±20 mg/dL; n = 7）患者和正常胆固醇血症（LDL-C水平，86.1±21 mg/dL; P<0.001; n = 7）对照个体分离的血浆LDL样品通过色谱法解析为5个亚组分，L1-L5。 患者组和对照组的L5百分比（L5%）和血浆L5浓度（[L5]=L5% × LDL-C）分别为8.1±2% vs. 2.3±1%（P<0.001）和12.6±4 mg/dL vs. 1.9±1 mg/dL（P<0.001）。 在接受阿托伐他汀治疗6个月（10 mg/天）的高胆固醇血症患者中，[L5]从12.6±4 mg/dL降至4.5±1.1 mg/dL（P = 0.011; n = 5），而2例不依从患者在停药3个月后[L5]和L5%均恢复至基线水平。 在培养的人主动脉内皮细胞（HAECs）中，L5以剂量和时间依赖性方式上调CRP表达达2.5倍（P<0.01），而最小电负性亚组分L1则无影响。DiI标记的L1通过LDL受体内化，在30秒内在HAEC内可见。相反，DiI标记的L5，通过LOX-1内化，在5分钟后变得明显。L5诱导的CRP表达在30分钟时出现，并通过中和LOX-1而减弱。30分钟后，L5而不是L1诱导活性氧（ROS）的产生。ROS抑制剂N-乙酰半胱氨酸可抑制L5诱导的ROS和CRP的产生。我们的研究结果表明，CRP，L5和LOX-1形成一个循环机制，在动脉粥样硬化形成和阿托伐他汀降低血浆L5水平破坏血管毒性L5。
Increased plasma C-reactive protein (CRP) levels are associated with the occurrence and severity of acute coronary syndrome. We investigated whether CRP can be generated in vascular endothelial cells (ECs) after exposure to the most electronegative subfraction of low-density lipoprotein (LDL), L5, which is atherogenic to ECs. Because L5 and CRP are both ligands for the lectin-like oxidized LDL receptor-1 (LOX-1), we also examined the role of LOX-1. Plasma LDL samples isolated from asymptomatic hypercholesterolemic (LDL cholesterol [LDL-C] levels, 154.6±20 mg/dL; n = 7) patients and normocholesterolemic (LDL-C levels, 86.1±21 mg/dL; P<0.001; n = 7) control individuals were chromatographically resolved into 5 subfractions, L1-L5. The L5 percentage (L5%) and the plasma L5 concentration ([L5] = L5% × LDL-C) in the patient and control groups were 8.1±2% vs. 2.3±1% (P<0.001) and 12.6±4 mg/dL vs. 1.9±1 mg/dL (P<0.001), respectively. In hypercholesterolemic patients treated with atorvastatin for 6 months (10 mg/day), [L5] decreased from 12.6±4 mg/dL to 4.5±1.1 mg/dL (P = 0.011; n = 5), whereas both [L5] and L5% returned to baseline levels in 2 noncompliant patients 3 months after discontinuation. In cultured human aortic ECs (HAECs), L5 upregulated CRP expression in a dose- and time-dependent manner up to 2.5-fold (P<0.01), whereas the least electronegative subfraction, L1, had no effect. DiI-labeled L1, internalized through the LDL receptor, became visible inside HAECs within 30 seconds. In contrast, DiI-labeled L5, internalized through LOX-1, became apparent after 5 minutes. L5-induced CRP expression manifested at 30 minutes and was attenuated by neutralizing LOX-1. After 30 minutes, L5 but not L1 induced reactive oxygen species (ROS) production. Both L5-induced ROS and CRP production were attenuated by ROS inhibitor N-acetyl cysteine. Our results suggest that CRP, L5, and LOX-1 form a cyclic mechanism in atherogenesis and that reducing plasma L5 levels with atorvastatin disrupts the vascular toxicity of L5.
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