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. 2022 Sep 20;9:988266. doi: 10.3389/fcvm.2022.988266

FIGURE 2.

FIGURE 2

NF-κB and ER stress in three phases of AS. (A) Atherogenesis. Endothelial dysfunction as an initial event in atherogenesis is induced by NF-κB and downstream inflammatory mediators. The SREBP pathway is induced by ER stress and aggravates endothelial dysfunction. SREBP- and NF-κB-induced NLRP3 inflammasome contributes to atherogenesis. Chemokines induced by NF-κB attract lymphocytes and trigger endothelial inflammation. NF-κB also promotes the recruitment and differentiation of monocytes by increasing the levels of adhesion molecules and M-CSF of endothelial cells. After differentiated into macrophages, UPR markers are activated, which protects macrophages from ER stress-induced apoptosis. (B) Plaque progression. This phase is characterized by foam cell formation, VSMC migration and proliferation, ECM accumulation, and NC formation. ROS/NF-κB regulates the migration and phenotypic switch of VSMCs. Circ-Sirt1 inhibits NF-κB and thus alleviates the progression of AS. Macrophages uptake oxLDL via CD36 and this triggers the NF-κB signaling pathways, which promotes the transformation into foam cells. XBP-1 also regulates foam cell formation, endothelial apoptosis and VSMC calcification. Inhibition of ER stress promotes the formation of M1 subtype and subsequent foam cell formation. In macrophages, activated NLRP3 inflammasome causes pyroptosis and apoptosis via caspase. (C) Plaque rupture. This phase is characterized by less SMCs and collagen, and more lipids and macrophages, which could involve NF-κB-FasL pathway. Macrophages induce plaque rupture by secreting MMPs, which is regulated by TLR4/NF-κB and RAGE/NF-κB signaling. Apoptosis of macrophages and VSMCs is induced by the prolonged ER stress, including PERK and IRE-XBP1. CHOP is also a mediator of apoptosis, vascular remodeling and plaque necrosis, whose expression is promoted by UPR signaling. Nrf2, as a synergistic mediator between NF-κB and ER stress, has an athero-protective role by upregulating some antioxidant enzymes. Additionally, NLRP3 inflammasome-mediated up-regulation of MMPs predisposes plaque to rupture.