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

Figure 1

ER stress-induced apoptosis in lesional macrophages and ECs. When the UPR fails to normalize ER function, prolonged ER stress will activate the proapoptotic pathway and eventually induce apoptosis. This mainly involves the following mechanisms in macrophages: (1) CHOP mediates activation of the ERO1/IP3R1/CaMK II calcium signaling pathway and its downstream apoptotic pathway. (2) CHOP regulates the Bcl-2 family, which controls the balance between the proapoptotic and antiapoptotic signals, thus controlling apoptosis. (3) The IRE1/TRAF2 complex interacts with ASK1 to induce JNK activation and then regulates Bcl-2 family members to promote cell apoptosis. (4) Calcium homeostasis imbalance and IRE1/TRAF2 activate the caspase-12 cascade, which eventually induces apoptosis. (5) The coinduction of low-dose ER stressors and atherorelevant second hits, such as the activation of PRRs, led to macrophage apoptosis. In ECs (red arrows), CHOP-mediated imbalance of the Bcl-2 family activated proapoptotic proteins on the mitochondrial membrane to induce the release of cytochrome c, leading to subsequent mitochondrial-dependent apoptosis. This process, together with calcium homeostasis imbalance, leads to decreased mitochondrial function and increased levels of NADPH and ROS in ECs under the pathological conditions of atherosclerosis, thus causing apoptosis and vascular endothelial dysfunction. CaMK II: calcium/calmodulin-dependent protein kinase II; STAT1: signal transducer and activator of transcription 1; PRRs: pattern recognition receptors.