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.

中文翻译：

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Vav家族蛋白的三个成员形成复合物，有助于泡沫细胞形成和动脉粥样硬化。

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在脂质摄取和通过Vav分子激活触发动脉粥样硬化中起关键作用。Vav家族包含三个高度保守的成员，分别称为Vav1，Vav2和Vav3。由于发现了Vav1和Vav3在动脉粥样硬化的发展中发挥作用，因此仍然需要判断Vav2是否也在动脉粥样硬化的发展中起作用。在这项研究中，我们发现RAW264.7巨噬细胞中的Vav2缺陷显着减少了氧化的LDL摄取和CD36信号传导，表明泡沫细胞形成需要每个Vav蛋白家族成员。ApoE缺陷型C57BL / 6小鼠中Vav2的遗传破坏显着抑制了动脉粥样硬化的严重性。惊人地 我们进一步发现，CRISPR / Cas9对Vav蛋白家族每个成员的遗传删除导致巨噬细胞转录组谱的相似改变。Vav蛋白的三个成员被发现形成复合物，并且每个Vav分子的遗传消融足以防止CD36的内吞。三个Vav家族成员在泡沫细胞形成中的功能相互依赖性是由于它们在巨噬细胞的转录组编程，脂质摄取和JNK激酶激活中起着不可或缺的作用。