Negre-Salvayre Anne, Vieira Otilia, Escargueil-Blanc Isabelle, Salvayre Robert
INSERM U-466, IFR-31, University Paul Sabatier, Bât L3, CHU Rangueil--Avenue Jean Poulhes, TSA 532--31059, Toulouse cedex 9, France.
Mol Aspects Med. 2003 Aug-Oct;24(4-5):251-61. doi: 10.1016/s0098-2997(03)00020-7.
Among the diverse risk factors involved in atherosclerosis, LDL are thought to become atherogenic after undergoing oxidative modifications, characterized by oxidized lipid formation and structural alterations of apoB. Oxidized LDL alter various signaling pathways and exhibit a broad range of biological responses including inflammation, gene expression, cell proliferation or apoptosis. The biological effects of oxidized LDL are related to the presence of peroxidation products such as hydroperoxides, lysophosphatidylcholines, oxysterols and aldehydes.4-Hydroxynonenal (HNE) is one of the most abundant aldehydes formed during the oxidation of polyunsaturated fatty acids in LDL and in membranes. It is able to react with thiols and free amino group residues of proteins. HNE is involved in apoB modifications that alter LDL metabolism and cell protein-adduct formation which may mediate in part the biological effects of oxidized LDL. We report here that HNE delivered to cells by oxidized LDL reacts with cellular proteins, for instance with tyrosine kinase receptors (RTK) such as EGFR and PDGFR. HNE induces in vitro derivatization and tyrosine phosphorylation of RTK (the fine molecular mechanism and conformational changes remain to be elucidated). In intact living cells, oxidized LDL (and pure HNE) trigger HNE-adduct formation and activation of PDGFR and EGFR, through an antioxidant-insensitive and reactive oxygen species independent mechanism. The presence of HNE-PDGFR adducts in atherosclerotic areas lead one to hypothesize that oxidized lipids may also react in vivo with membrane RTK, thereby disturbing their cellular functions.
在动脉粥样硬化涉及的多种风险因素中，低密度脂蛋白（LDL）被认为在经历氧化修饰后会变得具有致动脉粥样硬化性，其特征是氧化脂质的形成和载脂蛋白B的结构改变。氧化型LDL改变各种信号通路，并表现出广泛的生物学反应，包括炎症、基因表达、细胞增殖或凋亡。氧化型LDL的生物学效应与过氧化产物如氢过氧化物、溶血磷脂酰胆碱、氧化甾醇和醛的存在有关。4-羟基壬烯醛（HNE）是LDL和细胞膜中多不饱和脂肪酸氧化过程中形成的最丰富的醛之一。它能够与蛋白质的硫醇和游离氨基残基反应。HNE参与载脂蛋白B的修饰，改变LDL代谢和细胞蛋白加合物的形成，这可能部分介导氧化型LDL的生物学效应。我们在此报告，由氧化型LDL传递给细胞的HNE与细胞蛋白反应，例如与酪氨酸激酶受体（RTK）如表皮生长因子受体（EGFR）和血小板衍生生长因子受体（PDGFR）反应。HNE在体外诱导RTK的衍生化和酪氨酸磷酸化（精确的分子机制和构象变化仍有待阐明）。在完整的活细胞中，氧化型LDL（和纯HNE）通过一种不依赖抗氧化剂和活性氧的机制触发HNE加合物的形成以及PDGFR和EGFR的激活。动脉粥样硬化区域中HNE-PDGFR加合物的存在使人们推测氧化脂质在体内也可能与膜RTK反应，从而干扰其细胞功能。
