最近的研究表明,循环LDL(低密度脂蛋白)在动脉粥样硬化的发病机制中起着核心作用。氧化形式(ox-LDL)是高度致动脉粥样硬化的。在动脉粥样硬化斑块中发现了ox-LDL的沉积物,和ox-LDL已经被证明可以促进单核细胞募集,泡沫细胞的形成以及静止和收缩血管SMC(平滑肌细胞)向迁移和增殖表型的转变。SMC表型转变和增生是动脉粥样硬化发病的关键事件。为了理解ox-LDL介导的SMC表型转变的复杂分子机制,我们使用AffymetrixHG-133UAcDNA微阵列芯片比较了培养的静止人冠状动脉SMC与ox-LDL诱导3和21小时的细胞的差异基因表达谱。将受调控的基因分配到功能组中,表明有几个基因参与代谢,膜运输,细胞-细胞相互作用,信号转导,转录,翻译,细胞迁移,增殖和凋亡差异表达。我们的数据表明,ox-LDL与其同源受体在SMC上的相互作用调节了几种生长因子和细胞因子的诱导,激活多种细胞内信号机制(包括PI3K,MAPK,Jak/STAT,鞘氨醇,Rho激酶途径)有助于SMC从静止和收缩表型转变为增殖和迁移表型。我们的研究还确定了几个基因(包括CDC27,细胞周期蛋白A1,细胞周期蛋白G2,磷脂酰肌醇蛋白聚糖1,MINOR,p15和载脂蛋白)先前未涉及ox-LDL诱导的SMC表型转变,并且大大扩展了与动脉粥样硬化有关的潜在候选基因列表。
Recent studies suggest that circulating LDL (low-density lipoproteins) play a central role in the pathogenesis of atherosclerosis, and the oxidized form (ox-LDL) is highly atherogenic. Deposits of ox-LDL have been found in atherosclerotic plaques, and ox-LDL has been shown to promote monocyte recruitment, foam cell formation and the transition of quiescent and contractile vascular SMCs (smooth muscle cells) to the migratory and proliferative phenotype. SMC phenotype transition and hyperplasia are the pivotal events in the pathogenesis of atherosclerosis. To comprehend the complex molecular mechanisms involved in ox-LDL-mediated SMC phenotype transition, we have compared the differential gene expression profiles of cultured quiescent human coronary artery SMCs with cells induced with ox-LDL for 3 and 21 h using Affymetrix HG-133UA cDNA microarray chips. Assignment of the regulated genes into functional groups indicated that several genes involved in metabolism, membrane transport, cell-cell interactions, signal transduction, transcription, translation, cell migration, proliferation and apoptosis were differentially expressed. Our data suggests that the interaction of ox-LDL with its cognate receptors on SMCs modulates the induction of several growth factors and cytokines, which activate a variety of intracellular signalling mechanisms (including PI3K, MAPK, Jak/STAT, sphingosine, Rho kinase pathways) that contribute to SMC transition from the quiescent and contractile phenotype to the proliferative and migratory phenotype. Our study has also identified several genes (including CDC27, cyclin A1, cyclin G2, glypican 1, MINOR, p15 and apolipoprotein) not previously implicated in ox-LDL-induced SMC phenotype transition and substantially extends the list of potential candidate genes involved in atherogenesis.