Figure 4.

Differential effects of HO-1 and NRF2 in atherosclerosis. Prooxidant and proatherogenic stimuli such as oxLDL and oxPAPC can induce HO-1 expression in vascular cells via Nrf2 activation or other pathways. HO-1 expression leads to decreased ROS generation, decreased inflammatory events such as lower expression of cell adhesion molecules (CAMs) and decreased secretion of inflammatory factors such as monocyte chemotactic protein (MCP)-1 and IL-8. HO-1 also leads to decreased foam cell formation and changes in LDL and HDL lipoproteins, all of which lead to decreased atherogenesis. Nrf2 is bound by chaperone Keap1 in the cytosol. Electrophilic agents lead to dissociation of the Nrf2-Keap1 complex, with release of Nrf2 and nuclear translocation that leads to the induction of HO-1 and several other antioxidant genes that result in decreased ROS formation. However, Nrf2 expression promotes atherosclerotic lesion development. Possible mechanisms include: (1) increased macrophage lipid uptake and foam cell formation, (2) increased lipogenesis and greater levels of non-HDL plasma cholesterol, (3) greater macrophage secretion of IL-1 and monocyte migration to the vessels, and (4) possible macrophage differentiation into a proatherosclerotic phenotype.