Université Pierre et Marie Curie-Paris 6, Paris, France; AP-HP, Groupe hospitalier Pitié-Salpétrière, Paris, France; National Institute for Health and Medical Research (INSERM), Paris, France.
AP-HP, Groupe hospitalier Pitié-Salpétrière, Paris, France.
J Clin Lipidol. 2016 Jan-Feb;10(1):124-33. doi: 10.1016/j.jacl.2015.10.006. Epub 2015 Oct 17.
Familial hypercholesterolemia (FH) features elevated oxidative stress and accelerated atherosclerosis driven by elevated levels of atherogenic lipoproteins relative to subnormal levels of atheroprotective high-density lipoprotein (HDL). Small, dense HDL3 potently protects low-density lipoprotein (LDL) against proinflammatory oxidative damage.
To determine whether antioxidative and/or anti-inflammatory activities of HDL are defective in FH and whether such defects are corrected by LDL apheresis.
Antioxidative and antiinflammatory activities of HDL were evaluated as protection of reference LDL from oxidative stress and capacity to prevent accumulation of proinflammatory oxidised lipids, respectively. Lipid surface rigidity of HDL was assessed using a fluorescent probe. HDL components were measured by analytical approaches. Systemic oxidative stress was characterized as plasma 8-isoprostanes.
Pre-LDL-apheresis, FH patients (n = 10) exhibited elevated systemic oxidative stress (3.3-fold, P < 0.001) vs. sex- and age-matched normolipidemic controls (n = 10). Both antioxidative and antiinflammatory activity of HDL3 were impaired (up to -91%, P < 0.01) in FH. Sphingomyelin and saturated fatty acid contents were elevated in FH HDL3, resulting in enhanced lipid surface rigidity. The surface lipid content (phospholipids, free cholesterol) was reduced in FH (up to -15%, P < 0.001), whereas content of core lipids (cholesteryl esters, triglycerides) was elevated (up to +17%, P < 0.001). Molar apolipoprotein A-I content of HDL3 was subnormal in FH. A single LDL-apheresis session partially corrected (by up to 76%) deficient HDL antiatherogenic activities, attenuated systemic oxidative stress and partially normalised both the lipid composition and surface rigidity of HDL particles.
FH features elevated oxidative stress and deficient antioxidative and anti-inflammatory activities of small, dense HDL3; such functional deficiency is intimately linked to anomalies in lipid and protein composition, which may impair the capacity of HDL to acquire and inactivate oxidized lipids.
家族性高胆固醇血症 (FH) 的特征是由于致动脉粥样硬化脂蛋白水平升高而导致氧化应激升高和动脉粥样硬化加速，而保护性高密度脂蛋白 (HDL) 水平低于正常水平。小而密的 HDL3 可有效保护 LDL 免受促炎氧化损伤。
确定 FH 中 HDL 的抗氧化和/或抗炎活性是否存在缺陷，以及 LDL 吸附是否可以纠正这些缺陷。
通过分别评估保护参考 LDL 免受氧化应激和防止促炎氧化脂质积累的能力，来评估 HDL 的抗氧化和抗炎活性。使用荧光探针评估 HDL 的脂质表面刚性。通过分析方法测量 HDL 成分。通过血浆 8-异前列腺素来描述系统性氧化应激。
在 LDL 吸附前，FH 患者（n=10）表现出比性别和年龄匹配的正常脂质血症对照组（n=10）高 3.3 倍的系统性氧化应激（P<0.001）。FH 患者的 HDL3 的抗氧化和抗炎活性均受损（最多 -91%，P<0.01）。FH HDL3 中的鞘磷脂和饱和脂肪酸含量升高，导致脂质表面刚性增强。FH 中 HDL 的表面脂质含量（磷脂、游离胆固醇）降低（最多 -15%，P<0.001），而核心脂质含量（胆固醇酯、甘油三酯）升高（最多 +17%，P<0.001）。FH 中的 HDL3 载脂蛋白 A-I 摩尔含量低于正常水平。单次 LDL 吸附可部分纠正（最多 76%）HDL 的抗动脉粥样硬化活性缺陷，减轻系统性氧化应激，并部分正常化 HDL 颗粒的脂质组成和表面刚性。
FH 具有升高的氧化应激和小而密的 HDL3 的抗氧化和抗炎活性缺陷；这种功能缺陷与脂质和蛋白质组成的异常密切相关，这可能会损害 HDL 摄取和失活氧化脂质的能力。
