Role of Endoplasmic Reticulum Stress in Atherosclerosis and Diabetic Macrovascular Complications

Figure 1

The adaptive and proapoptotic UPR pathways. (a) Adaptive UPR mechanism. In nonstressed conditions, the ER chaperone GRP78 binds to all three ER stress sensors such as PERK, IRE1, and ATF6. In ER stress, GRP78 dissociates from the ER sensors, and this leads to their activation. eIF2α is phosphorylated by PERK and dephosphorylated by GADD34. Phosphorylated eIF2α blocks global protein translation but remains selective translation of several proteins including transcriptional factor ATF4. ATF4 then initiates expression of UPR-related genes. Upon activation, ATF6 translocates from the ER to the Golgi complex where it is cleaved by proteases S1P and S2P. Cleaved ATF6 acts as a transcriptional factor activating expression of several UPR- and non-UPR genes including XBP1. Activated IRE1 specifically splices XBP1 mRNA. Spliced XBP1 shows transcription factor activity to induce UPR- and non-UPR genes. Proteasome plays an important role in degradation of unfolded and misfolded proteins. Thus, production of proteasome components is also stimulated to increase utilization of misfolded proteins through the mechanism of ERAD. (b) Proapoptotic UPR mechanism. The apoptotic pathway is induced in chronic and prolonged ER stress. CHOP plays a key role in mediating ER stress-induced apoptosis. CHOP expression is stimulated by ATF4- and ATF6. CHOP represses expression of antiapoptotic proteins Bcl-2 and Bnip3 and activates translocation of proapoptotic protein Bim to the ER membrane. IRE1α forms a complex with the adaptor protein TRAF2, which consequently activates ASK1 and JNK. Activation of JNK induces apoptosis cell through phosphorylation of several Bcl-2 family members. The IRE1α/TRAF2 complex also binds to IκB kinase, and this results in activation of transcription factor NF-κB. Prolonged ER stress activates caspase 12 that in turn activates caspase-9/3 thereby leading to the mitochondria-independent apoptotic pathway.