Role of Endoplasmic Reticulum Stress in Atherosclerosis and Its Potential as a Therapeutic Target

Figure 2

ER stress-induced inflammation in macrophages and ECs. Under ER stress conditions in macrophages and ECs, the three ER stress sensors, PERK, IRE1, and ATF6, can all activate the NF-κB pathway and induce specific inflammatory responses. In addition, IRE1 induces the elevation of TXNIP, thereby activating the NLRP3 inflammasome, which in turn promotes caspase-1 activation and IL-1β and IL-18 secretion and an inflammatory response. RIP1 may be involved in this activation process. Under ER stress, increased calcium release leads to increased intracellular production of ROS, which is partly attenuated by the PERK-mediated transcription factor Nrf2 antioxidant program, but increased ROS levels may still lead to inflammation, contribute to NLRP3 activation to some extent, and promote ER dysfunction. XBP1s and ATF4 induce the production of inflammatory cytokines IL-8, IL-6, MCP1, and TNF-α. These all lead to inflammation and are involved in the development of atherosclerosis. ERO1: endoplasmic reticulum oxidoreductin 1; IP3R1: inositol 1,4,5-trisphosphate receptor type 1; Nrf2: nuclear factor erythroid 2-related factor-2; ROS: reactive oxygen species; MCP1: monocyte chemoattractant protein 1; TRAF2: tumor necrosis factor receptor-associated factor-2; ASK1: apoptosis signal-regulating kinase 1; JNK: c-Jun N-terminal kinase; IκB: inhibitor of nuclear factor-κB; IKK: IκB kinase; NF-κB: nuclear factor-κB; RIP1: kinase receptor-interacting protein 1; TXNIP: thioredoxin-interacting protein.