The three members of the Vav family proteins form complexes that concur to foam cell formation and atherosclerosis[S]
The three members of the Vav family proteins form complexes that concur to foam cell formation and atherosclerosis[S]
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Vav 家族蛋白的三个成员形成复合物，促进泡沫细胞形成和动脉粥样硬化
DOI：
10.1194/jlr.m094771
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发表时间：
2019-12-01
影响因子：
6.5
通讯作者：
Zhang, Lichen
中科院分区：
文献类型：
--
作者：
Huang, Rong;Guo, Guo;Zhang, Lichen
在泡沫细胞形成和动脉粥样硬化发展过程中，清道夫受体CD36通过激活Vav分子在脂质摄取和引发动脉粥样硬化中起关键作用。Vav家族包括三个高度保守的成员，分别是Vav1、Vav2和Vav3。由于Vav1和Vav3在动脉粥样硬化的发展中发挥作用，因此Vav2是否也在动脉粥样硬化的发展中发挥作用尚不清楚。在本研究中，我们发现RAW264.7巨噬细胞中Vav2缺乏显著降低氧化LDL摄取和CD36信号，表明每个Vav蛋白家族成员都是泡沫细胞形成所必需的。apoe缺陷C57BL/6小鼠的Vav2基因破坏可显著抑制动脉粥样硬化的严重程度。引人注目的是，我们进一步发现CRISPR/Cas9基因缺失Vav蛋白家族的每个成员导致巨噬细胞的转录组谱发生类似的改变。发现Vav蛋白的三个成员形成复合物，每个Vav分子的基因消融足以阻止CD36的内吞作用。三个Vav家族成员在泡沫细胞形成中的功能相互依赖是由于它们在巨噬细胞的转录组编程、脂质摄取和JNK激酶激活中不可或缺的作用
During foam cell formation and atherosclerosis development, the scavenger receptor CD36 plays critical roles in lipid uptake and triggering of atherogenicity via the activation of Vav molecules. The Vav family includes three highly conserved members known as Vav1, Vav2, and Vav3. As Vav1 and Vav3 were found to exert function in atherosclerosis development, it remains thus to decipher whether Vav2 also plays a role in the development of atherosclerosis. In this study we found that Vav2 deficiency in RAW264.7 macrophages significantly diminished oxidized LDL uptake and CD36 signaling, demonstrating that each Vav protein family member was required for foam cell formation. Genetic disruption of Vav2 in ApoE-deficient C57BL/6 mice significantly inhibited the severity of atherosclerosis. Strikingly, we further found that the genetic deletion of each member of the Vav protein family by CRISPR/Cas9 resulted in a similar alteration of transcriptomic profiles of macrophages. The three members of the Vav proteins were found to form complexes, and genetic ablation of each single Vav molecule was sufficient to prevent endocytosis of CD36. The functional interdependence of the three Vav family members in foam cell formation was due to their indispensable roles in transcriptomic programing, lipid uptake, and activation of the JNK kinase in macrophages.-