Targeting the Endoplasmic Reticulum Unfolded Protein Response to Counteract the Oxidative Stress-Induced Endothelial Dysfunction

Figure 2

The oxidative and antioxidant programmes of UPR. The antioxidant (green lines) and oxidative (red lines) pathways of UPR are depicted on the left or on the right, respectively. The PERK and IRE1α/XBP1 pathways promote the maintenance of ER proteostasis as follows. (1) There is PERK-mediated activation of the antioxidant transcription factor NRF2 and the promotion of GSH synthesis [45]. (2) There is IRE1α/XBP1-mediated induction of the hexosamine biosynthetic pathway (HBP), which is important for the production of UDP-GlcNAc [41]. On the right, the ER stress-dependent amplification of ROS production (red lines) is depicted. (3) Following ER stress, the increased folding activity of ER augments ROS production. (4) The ER stress increases the MAM-mediated calcium flux to mitochondria that inhibits ETC and increases mitochondrial ROS production; moreover, reduced ATP synthesis from the impaired ETC affects SERCA activity and the consequent ER calcium content which in turn boosts up unfolding [143]. (5) CHOP, through the induction of Ero1, potentiates calcium efflux from the ER. The higher cytosolic calcium activates the Ca²⁺/calmodulin-dependent protein kinase II- (CaMKII-) JNK-NOX-protein kinase R (PKR) pathway, which in turn positively feedbacks on CHOP expression [47, 57]. In addition, Ero1-increased expression potentiates the oxidative protein folding and ROS production. (6) Through microRNA inhibition, the RIDD activity of IRE1 relieves the expression of TXNIP protein that blocks the antioxidant enzyme TRX [50]. (7) IRE1α activates the tumor necrosis factor α-associated receptor 2 (TRAF2)/ASK1/JNK pathway that further upregulates the NOX-dependent ROS production [48, 144]. For detailed discussion and references, see the text. Red: reduced; Ox: oxidized; TRX: thioredoxin.