Figure 2. Oxidized LDL and OxPL induce ROS generation in vascular cells.

In macrophages, OxLDL binding to CD36 induces recruitment of Lyn, a Src kinase, its activation and phosphorylation of Vav, which in turn activates Rac ⁷⁴. Unlike OxLDL, mmLDL induces recruitment of Syk to TLR4 and Syk-dependent activation of Vav and Rac ⁹. In addition, mmLDL induces TLR4- and Syk-dependent activation of PLCγand PKC, which induces recruitment of p47phox, and p67phox (not shown) to the Nox2 enzyme complex, and activated (GTP-bound) Rac completes the complex, leading to ROS production ⁹,¹¹⁰. High levels of extracellular ROS may exacerbate the oxidative damage, while intracellular ROS are important signaling molecules, mediating cytokine secretion. One of mmLDL-induced, Nox2-dependent chemokines, RANTES, induces VSMC migration ¹¹⁰. Nox4 is the predominant NADPH oxidase in endothelial cells. It is activated by OxPAPC via VEGFR2-dependent Rac recruitment ¹⁰⁷. However, the mechanism of the OxPAPC activation is unclear. Although OxPAPC is capable of inducing VEGF production by endothelial cells ¹⁰³, anti-VEGF antibodies do not block OxPAPC activation of VEGFR2 ¹⁰⁷. ROS in endothelial cells mediate secretion of MCP-1 and IL-8 and thereby promote monocyte migration.