Vav proteins are mechanistically involved in CD36‐dependent atherogenic processes

Abstract

Activation of a CD36‐dependent signaling cascade is necessary for macrophage uptake of oxidatively modified LDL (oxLDL) and foam cell formation, and hence plays an important role in atherogenesis. We now show that CD36 contributes to activation of Vav family guanine nucleotide exchange factors (GEFs) in aortae from hyperlipidemic mice, and that oxLDL induces activation of macrophage Vav in vitro in a CD36 and Src family kinase‐dependent manner. CD36‐dependent uptake of oxLDL in vitro and foam cell formation in vivo was significantly reduced in Vav null macrophages concomitant with impaired calcium signaling and PLC‐gamma1 activation. Chelation of intracellular Ca2+ or inhibition of PLC‐gamma inhibited Vav activation and reduced foam cell formation. Inhibition of dynamin, a Vav interacting protein involved in endocytic vesicle fission, blocked oxLDL uptake and inhibited foam cell formation. Immunofluorescence microscopy studies showed that Vav1 and dynamin‐2 colocalized with internalized oxLDL in vitro and in atherosclerotic lesions in vivo, that mobilization of dynamin‐2 by oxLDL was impaired in Vav null cells, and that disruption of the CD36/Vav pathway caused a defect in maturation of oxLDL‐containing endocytic vesicle. These studies link CD36 and Vavs in a mechanistic signaling pathway required for macrophage foam cell formation and atherogenesis.