Vav Guanine nucleotide exchange factors regulate atherosclerotic lesion development in mice.
Vav Guanine nucleotide exchange factors regulate atherosclerotic lesion development in mice.
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DOI：
10.1161/atvbaha.113.301414
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发表时间：
2013-09
期刊：
影响因子：
--
通讯作者：
Silverstein RL
中科院分区：
文献类型：
--
作者：
Rahaman SO;Li W;Silverstein RL
Atherosclerosis requires migration of monocytes to the arterial intima with subsequent differentiation into foam cells. We showed previously that the scavenger receptor CD36 contributes to activation of Vav family guanine nucleotide exchange factors (Vavs) in aortae from hyperlipidemic apoe null mice, and that oxidatively modified LDL (oxLDL) induced CD36-dependent activation of macrophage Vavs in vitro. We also discovered that CD36-dependent uptake of oxLDL and foam cell formation were reduced in Vav-deficient macrophages. We now tested the hypothesis that Vavs play a role in atherosclerotic lesion development. We showed that apoe/vav1 double null mice fed a western diet had significant reduction in total aortic lesion area (by en face analysis) compared with apoe null mice with no significant differences in body weight or plasma lipid profiles. Histologic analysis of aortic sinus lesions showed fewer macrophages and foam cells in double null mice compared to apoe null, indicating impaired foam cell generation and/or homing of macrophages to atherosclerotic lesions. An intravital video microscopy-based adhesion assay with fluorescent (Qtracker655)-labeled monocytes showed reduced adhesion of vav1 null monocytes to hyperlipidemic carotid arteries compared to WT monocytes. Furthermore, fewer fluorescently labeled vav1 null monocytes accumulated in aortic sinus lesions in hyperlipidemic apoe null mice. We also found that activation of RhoGTPase Rac and MAP kinase c-Jun N-terminal kinase-2 (JNK2) by CD36-specific oxidized phospholipids was dependent on Vavs. These results for the first time link Vavs to atherosclerotic lesion development and suggest that Vavs act as critical molecular links coupling hyperlipidemia with pro-atherogenic monocyte/macrophage responses.
