Mildly Oxidized LDL Induces Activation of Platelet-Derived Growth Factor &bgr;-Receptor Pathway
Mildly Oxidized LDL Induces Activation of Platelet-Derived Growth Factor &bgr;-Receptor Pathway
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轻度氧化的低密度脂蛋白诱导血小板衍生生长因子的激活
作者：
I. Escargueil‐Blanc;R. Salvayre;N. Vacaresse;G. Jürgens;B. Darblade;J. Arnal;S. Parthasarathy;A. Nègre
背景-轻度氧化LDL （moxLDL）被认为在动脉粥样硬化中起作用。MoxLDL诱导细胞蛋白衍生化并触发多种细胞内信号传导。我们的目的是研究moxldl诱导的蛋白质衍生化是否会影响血小板衍生生长因子受体的活性；（PDGFR&bgr;），一种酪氨酸激酶受体，在血管生物学和动脉粥样硬化发生中起重要作用。方法与结果：moxLDL诱导兔动脉平滑肌细胞PDGFR&bgr的活化；信号通路，如PDGFR&bgr；酪氨酸磷酸化的Western blot和含sh2蛋白的共免疫沉淀。moxldl诱导PDGFR&bgr的细胞事件；激活可以总结如下。moxLDL氧化脂质触发两相pdgfr；激活涉及两种不同的机制，如在培养细胞（原位）和免疫纯化PDGFR&bgr上的实验所示；（体外）：(1)第一阶段可能由4-羟基壬烯醛介导，诱导PDGFR&bgr；加合物的形成和随后的PDGFR&bgr；活化（抗氧化剂不敏感步骤）；(2)第二阶段涉及神经酰胺介导的H2O2生成（这些步骤被神经酰胺形成抑制剂tosylphenylalanylchloromemethyl酮、抗氧化剂BHT、外源性过氧化氢酶或过表达的人过氧化氢酶所抑制）。因为4-hydroxynonenal-PDGFR&bgr;在动脉粥样硬化的主动脉中也检测到加合物，这表明低密度脂蛋白诱导pdgfr的新机制在动脉粥样硬化过程中可能发生活化。结论：moxldl在血管壁中充当局部自分泌介质，PDGFR&bgr；作为氧化脂质和氧化应激的传感器。这构成了PDGFR&bgr；动脉粥样硬化区激活。
Background—Mildly oxidized LDL (moxLDL) is thought to play a role in atherogenesis. MoxLDL induces derivatization of cell proteins and triggers a variety of intracellular signaling. We aimed to investigate whether moxLDL-induced protein derivatization may influence the activity of platelet-derived growth factor receptor &bgr; (PDGFR&bgr;), a tyrosine kinase receptor of major importance in vascular biology and atherogenesis. Methods and Results—In cultured rabbit arterial smooth muscle cells, moxLDL induces activation of the PDGFR&bgr; signaling pathway, as shown by PDGFR&bgr; tyrosine phosphorylation on Western blot and coimmunoprecipitation of SH2-containing proteins. The cellular events involved in the moxLDL-induced PDGFR&bgr; activation can be summarized as follows. Oxidized lipids from moxLDL trigger two phases of PDGFR&bgr; activation involving two separate mechanisms, as shown by experiments on cultured cells (in situ) and on immunopurified PDGFR&bgr; (in vitro): (1) the first phase may be mediated by 4-hydroxynonenal, which induces PDGFR&bgr; adduct formation and subsequent PDGFR&bgr; activation (antioxidant-insensitive step); (2) the second phase involves ceramide-mediated generation of H2O2 (these steps being inhibited by tosylphenylalanylchloromethylketone, an inhibitor of ceramide formation, and by antioxidant BHT, exogenous catalase, or overexpressed human catalase). Because 4-hydroxynonenal–PDGFR&bgr; adducts are also detected in atherosclerotic aortas, it is suggested that this novel mechanism of moxLDL-induced PDGFR&bgr; activation may occur during atherogenesis. Conclusions—MoxLDL acts as a local autoparacrine mediator in the vascular wall, and PDGFR&bgr; acts as a sensor for both oxidized lipids and oxidative stress. This constitutes a novel mechanism of PDGFR&bgr; activation in atherosclerotic areas.
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影响因子：
3.9
作者：
ROYALL, JA;ISCHIROPOULOS, H
通讯作者：
ISCHIROPOULOS, H
最低限度氧化的 LDL 刺激 Gs 并抑制 Gi 蛋白功能。
DOI：
10.1161/01.atv.15.11.2019
发表时间：
1995
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Parhami,F;Fang,ZT;Yang,B;Fogelman,AM;Berliner,JA
通讯作者：
Berliner,JA
人过氧化氢酶基因的过度表达降低了血管平滑肌细胞中氧化脂质诱导的细胞毒性。
DOI：
10.1161/01.atv.19.8.1912
发表时间：
1999
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Santanam,N;Aug,N;Zhou,M;Keshava,C;Parthasarathy,S
通讯作者：
Parthasarathy,S
超越胆固醇。
DOI：
10.1056/nejm198904063201407
发表时间：
1989
期刊：
The New England journal of medicine
影响因子：
--
作者：
Steinberg,D;Parthasarathy,S;Carew,TE;Khoo,JC;Witztum,JL
通讯作者：
Witztum,JL
平滑肌细胞中氧化低密度脂蛋白介导的磷脂酶 D 激活：在细胞增殖和动脉粥样硬化形成中的可能作用。
影响因子：
6.5
作者：
Natarajan,V;Scribner,WM;Hart,CM;Parthasarathy,S
通讯作者：
Parthasarathy,S