Malden L T, Chait A, Raines E W, Ross R
Department of Pathology, University of Washington, Seattle 98195.
J Biol Chem. 1991 Jul 25;266(21):13901-7.
Platelet-derived growth factor (PDGF) is secreted by several cells that participate in the process of atherogenesis, including arterial wall monocyte-derived macrophages. Macrophages in human and non-human primate lesions have recently been demonstrated to contain PDGF-B chain protein in situ. In developing lesions of atherosclerosis, macrophages take up and metabolize modified lipoproteins, leading to lipid accumulation and foam cell formation. Oxidatively modified low density lipoproteins (LDL) have been implicated in atherogenesis and have been demonstrated in atherosclerotic lesions. The effects of the uptake of various forms of modified LDL on PDGF gene expression, synthesis, and secretion in adherent cultures of human blood monocyte-derived macrophages were examined. LDL oxidized in a cell-free system in the presence of air and copper inhibited the constitutive expression of PDGF-B mRNA and secretion of PDGF in a dose-dependent fashion. Oxidatively modified LDL also attenuated lipopolysaccharide-induced PDGF-B mRNA expression. These changes were unrelated to the mechanism of lipid uptake and the degree of lipid loading and were detectable within 2 h of exposure to oxidized LDL. The degree of inhibition of both basal and lipopolysaccharide-induced PDGF-B-chain expression increased with the extent of LDL oxidation. Monocyte-derived macrophages exposed to acetylated LDL or LDL aggregates accumulated more cholesterol than cells treated with oxidized LDL, but PDGF expression was not consistently altered. Thus, uptake of a product or products of LDL oxidation modulates the expression and secretion of one of the principal macrophage-derived growth factors, PDGF. This modulation may influence chemotaxis and mitogenesis of smooth muscle cells locally in the artery wall during atherogenesis.
血小板衍生生长因子（PDGF）由几种参与动脉粥样硬化形成过程的细胞分泌，包括动脉壁单核细胞衍生的巨噬细胞。最近已证实在人类和非人类灵长类动物病变中的巨噬细胞原位含有PDGF - B链蛋白。在动脉粥样硬化的发展病变中，巨噬细胞摄取并代谢修饰的脂蛋白，导致脂质积累和泡沫细胞形成。氧化修饰的低密度脂蛋白（LDL）与动脉粥样硬化形成有关，并已在动脉粥样硬化病变中得到证实。研究了各种形式的修饰LDL摄取对人血单核细胞衍生巨噬细胞贴壁培养中PDGF基因表达、合成和分泌的影响。在空气和铜存在下于无细胞系统中氧化的LDL以剂量依赖性方式抑制PDGF - B mRNA的组成性表达和PDGF的分泌。氧化修饰的LDL还减弱了脂多糖诱导的PDGF - B mRNA表达。这些变化与脂质摄取机制和脂质负载程度无关，并且在暴露于氧化LDL后2小时内即可检测到。基础和脂多糖诱导的PDGF - B链表达的抑制程度随LDL氧化程度的增加而增加。暴露于乙酰化LDL或LDL聚集体的单核细胞衍生巨噬细胞比用氧化LDL处理的细胞积累更多的胆固醇，但PDGF表达并未持续改变。因此，LDL氧化产物的摄取调节了主要的巨噬细胞衍生生长因子之一PDGF的表达和分泌。这种调节可能会影响动脉粥样硬化形成过程中动脉壁局部平滑肌细胞的趋化性和有丝分裂。
