eNOS Activation by HDL Is Impaired in Genetic CETP Deficiency
eNOS Activation by HDL Is Impaired in Genetic CETP Deficiency
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DOI：
10.1371/journal.pone.0095925
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发表时间：
2014-05-15
期刊：
影响因子：
3.7
通讯作者：
Calabresi, Laura
中科院分区：
文献类型：
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作者：
Gomaraschi, Monica;Ossoli, Alice;Calabresi, Laura
CETP基因突变导致CETP活性缺陷，已被证明会导致血浆HDL- c水平显著升高，血浆中积聚了富含载脂蛋白e的大而浮力的HDL颗粒，因此遗传性CETP缺乏是评估HDL结构改变如何影响HDL动脉粥样硬化保护功能的独特工具。本研究的目的是评估从cetp缺乏的受试者中获得的HDL保护内皮细胞免于内皮功能障碍的能力。从CETP零突变的1个纯合子和7个杂合子载体中分离的HDL被评估其下调细胞因子诱导的细胞粘附分子表达和促进培养内皮细胞NO生成的能力。在相同蛋白浓度下，来自携带者的HDL和HDL3在下调细胞因子诱导的VCAM-1的作用与对照组的HDL和HDL3一样有效，而来自携带者的HDL2在抑制VCAM-1表达方面比对照组的HDL2更有效。另一方面，来自CETP缺乏携带者的HDL和HDL组分在刺激NO生成方面的效果明显低于对照HDL和HDL组分，这可能是由于S1P含量降低导致eNOS激活能力降低。总之，目前的研究结果支持这样的观点，即遗传性CETP缺乏通过影响HDL颗粒结构，影响HDL血管保护功能。了解这些作用可能对预测药理学CETP抑制的结果很重要。
Mutations in the CETP gene resulting in defective CETP activity have been shown to cause remarkable elevations of plasma HDL-C levels, with the accumulation in plasma of large, buoyant HDL particles enriched in apolipoprotein E. Genetic CETP deficiency thus represents a unique tool to evaluate how structural alterations of HDL impact on HDL atheroprotective functions. Aim of the present study was to assess the ability of HDL obtained from CETP-deficient subjects to protect endothelial cells from the development of endothelial dysfunction. HDL isolated from one homozygous and seven heterozygous carriers of CETP null mutations were evaluated for their ability to down-regulate cytokine-induced cell adhesion molecule expression and to promote NO production in cultured endothelial cells. When compared at the same protein concentration, HDL and HDL3 from carriers proved to be as effective as control HDL and HDL3 in down-regulating cytokine-induced VCAM-1, while carrier HDL2 were more effective than control HDL2 in inhibiting VCAM-1 expression. On the other hand, HDL and HDL fractions from carriers of CETP deficiency were significantly less effective than control HDL and HDL fractions in stimulating NO production, due to a reduced eNOS activating capacity, likely because of a reduced S1P content. In conclusion, the present findings support the notion that genetic CETP deficiency, by affecting HDL particle structure, impacts on HDL vasculoprotective functions. Understanding of these effects might be important for predicting the outcomes of pharmacological CETP inhibition.