de Souza Juliana A, Vindis Cecile, Hansel Boris, Nègre-Salvayre Anne, Therond Patrice, Serrano Carlos V, Chantepie Sandrine, Salvayre Robert, Bruckert Eric, Chapman M John, Kontush Anatol
Université Pierre et Marie Curie-Paris 6, Paris F-75013, France.
Atherosclerosis. 2008 Mar;197(1):84-94. doi: 10.1016/j.atherosclerosis.2007.08.009. Epub 2007 Sep 14.
The metabolic syndrome (MetS) phenotype is typically characterized by visceral obesity, insulin resistance, atherogenic dyslipidemia involving hypertriglyceridemia and subnormal levels of high density lipoprotein-cholesterol (HDL-C), oxidative stress and elevated cardiovascular risk. The potent antioxidative activity of small HDL3 is defective in MetS [Hansel B, et al. J Clin Endocrinol Metab 2004;89:4963-71]. We evaluated the functional capacity of small HDL3 particles from MetS subjects to protect endothelial cells from apoptosis induced by mildly oxidized low-density lipoprotein (oxLDL). MetS subjects presented an insulin-resistant obese phenotype, with hypertriglyceridemia, elevated apolipoprotein B and insulin levels, but subnormal HDL-C concentrations and chronic low grade inflammation (threefold elevation of C-reactive protein). When human microvascular endothelial cells (HMEC-1) were incubated with oxLDL (200 microg apolipoprotein B/ml) in the presence or absence of control HDL subfractions (25 microg protein/ml), small, dense HDL3b and 3c significantly inhibited cellular annexin V binding and intracellular generation of reactive oxygen species. The potent anti-apoptotic activity of small HDL3c particles was reduced (-35%; p<0.05) in MetS subjects (n=16) relative to normolipidemic controls (n=7). The attenuated anti-apoptotic activity of HDL3c correlated with abdominal obesity, atherogenic dyslipidemia and systemic oxidative stress (p<0.05), and was intimately associated with altered physicochemical properties of apolipoprotein A-I (apoA-I)-poor HDL3c, involving core cholesteryl ester depletion and triglyceride enrichment. We conclude that in MetS, apoA-I-poor, small, dense HDL3c exert defective protection of endothelial cells from oxLDL-induced apoptosis, potentially reflecting functional anomalies intimately associated with abnormal neutral lipid core content.
代谢综合征（MetS）的表型通常具有以下特征：内脏肥胖、胰岛素抵抗、致动脉粥样硬化性血脂异常，包括高甘油三酯血症和高密度脂蛋白胆固醇（HDL-C）水平低于正常、氧化应激以及心血管风险升高。小HDL3的强大抗氧化活性在MetS中存在缺陷[汉塞尔B等人。《临床内分泌与代谢杂志》2004年；89：4963 - 71]。我们评估了来自MetS受试者的小HDL3颗粒保护内皮细胞免受轻度氧化的低密度脂蛋白（oxLDL）诱导的凋亡的功能能力。MetS受试者表现出胰岛素抵抗性肥胖表型，伴有高甘油三酯血症、载脂蛋白B和胰岛素水平升高，但HDL-C浓度低于正常以及慢性低度炎症（C反应蛋白升高三倍）。当人微血管内皮细胞（HMEC - 1）与oxLDL（200微克载脂蛋白B/毫升）在有或无对照HDL亚组分（25微克蛋白质/毫升）存在的情况下孵育时，小而致密的HDL3b和3c显著抑制细胞膜联蛋白V结合以及细胞内活性氧的产生。相对于血脂正常的对照组（n = 7），MetS受试者（n = 16）中小HDL3c颗粒的强大抗凋亡活性降低了（-35%；p<0.05）。HDL3c抗凋亡活性的减弱与腹部肥胖、致动脉粥样硬化性血脂异常和全身氧化应激相关（p<0.05），并且与载脂蛋白A - I（apoA - I）含量低得HDL3c的物理化学性质改变密切相关，包括核心胆固醇酯耗竭和甘油三酯富集。我们得出结论，在MetS中，apoA - I含量低的小而致密的HDL3c对内皮细胞免受oxLDL诱导的凋亡的保护作用存在缺陷，这可能反映了与异常中性脂质核心含量密切相关的功能异常。
