Suppression of endothelial cell apoptosis by high density lipoproteins (HDL) and HDL-associated lysophingolipids
Suppression of endothelial cell apoptosis by high density lipoproteins (HDL) and HDL-associated lysophingolipids
复制标题
DOI：
10.1074/jbc.m103782200
复制
发表时间：
2001-09-14
影响因子：
4.8
通讯作者：
Assmann, G
中科院分区：
文献类型：
--
作者：
Nofer, JR;Levkau, B;Assmann, G
血管内皮损伤后的细胞凋亡。被认为在动脉粥样硬化的发病机制中起重要作用。在这份报告中，我们证明了高密度脂蛋白（HDL），一个主要的抗动脉粥样硬化脂蛋白组分，保护内皮细胞免受生长因子剥夺诱导的凋亡。HDL通过抑制线粒体电位（Atom）的耗散、活性氧的产生和细胞色素c向细胞质的释放来阻断凋亡的线粒体途径。因此，HDL阻止了半胱天冬酶9和3的活化以及质膜的凋亡改变，如渗透性增加和磷脂酰丝氨酸的易位。用HDL处理内皮细胞诱导蛋白激酶Akt的活化，Akt是一种普遍存在的抗凋亡信号转导子，并导致BAD的磷酸化，BAD是Akt的主要底物。抑制Akt活性无论是渥曼青霉素和LY294002或显性负性Akt突变体废除HDL的抗凋亡作用。存在于HDL颗粒中的两种生物活性lysosphingolipids，鞘糖磷酸胆碱和lysosulfatide，通过阻断细胞凋亡的线粒体途径和有效地激活Akt来完全模拟HDL的存活效应。总之，本研究确定HDL作为内源性内皮细胞存活因子的载体，并表明HDL相关lysosphingolipids抑制内皮细胞凋亡可能代表HDL抗动脉粥样硬化活性的一个重要和新颖的方面。
Apoptotic cell death following injury of vascular endothelium. is assumed to play an important role in the pathogenesis of atherosclerosis. In this report, we demonstrate that high density lipoproteins (HDL), a major anti-atherogenic lipoprotein fraction, protect endothelial cells against growth factor deprivation-induced apoptosis. HDL blocked the mitochondrial pathway of apoptosis by inhibiting dissipation of mitochondrial potential (Atom), generation of reactive oxygen species, and release of cytochrome c into the cytoplasm. As a consequence, HDL prevented activation of caspases 9 and 3 and apoptotic alterations of the plasma membrane such as increase of permeability and translocation of phosphatidylserine. Treatment of endothelial cells with HDL induced activation of the protein kinase Akt, an ubiquitous transducer of anti-apoptotic signals, and led to phosphorylation of BAD, a major Akt substrate. Suppression of Akt activity both by wortmannin and LY294002 or by a dominant negative Akt mutant abolished the anti-apoptotic effect of HDL. Two bioactive lysosphingolipids present in HDL particles, sphingosylphosphorycholine and lysosulfatide, fully mimicked the survival effect of HDL by blocking the mitochondrial pathway of apoptosis and potently activating Akt. In conclusion, the present study identifies HDL as a carrier of endogenous endothelial survival factors and suggests that inhibition of endothelial apoptosis by HDL-associated lysosphingolipids may represent an important and novel aspect of the anti-atherogenic activity of HDL.