The UPR in atherosclerosis

Abstract

Multiple systemic factors and local stressors in the arterial wall can disturb the functions of endoplasmic reticulum (ER), causing ER stress in endothelial cells (ECs), smooth muscle cells (SMCs), and macrophages during the initiation and progression of atherosclerosis. As a protective response to restore ER homeostasis, the unfolded protein response (UPR) is initiated by three major ER sensors: protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α), and activating transcription factor 6 (ATF6). The activation of the various UPR signaling pathways displays a temporal pattern of activation at different stages of the disease. The ATF6 and IRE1α pathways that promote the expression of protein chaperones in ER are activated in ECs in athero-susceptible regions of pre-lesional arteries and before the appearance of foam cells. The PERK pathway that reduces ER protein client load by blocking protein translation is activated in SMCs and macrophages in early lesions. The activation of these UPR signaling pathways aims to cope with the ER stress and plays a pro-survival role in the early stage of atherosclerosis. However, with the progression of atherosclerosis, the extended duration and increased intensity of ER stress in lesions lead to prolonged and enhanced UPR signaling. Under this circumstance, the PERK pathway induces expression of death effectors, and possibly IRE1α activates apoptosis signaling pathways, leading to apoptosis of macrophages and SMCs in advanced lesions. Importantly, UPR-mediated cell death is associated with plaque instability and the clinical progression of atherosclerosis. Moreover, UPR signaling is linked to inflammation and possibly to macrophage differentiation in lesions. Therapeutic approaches targeting the UPR may have promise in the prevention and/or regression of atherosclerosis. However, more progress is needed to fully understand all of the roles of the UPR in atherosclerosis and to harness this information for therapeutic advances.

Fig. 1

Sequential activation of UPR signaling pathways in atherosclerosis. Endothelial cells (ECs) in athero-susceptible regions of pre-lesional arteries are primed for expression of ER chaperones with induced expression of ATF6, IRE1α, and XBP1. ER chaperones are expressed in both early and advanced atheroma, most likely as a compensatory response to restore ER homeostasis. The PERK pathway is activated in macrophages at all stages of atherosclerosis and in ECs and SMCs in advanced lesions. The early activation of the PERK pathway might be protective through suppression of protein synthesis, which reduces ER protein client load. However, sustained and enhanced PERK activation induces CHOP in advanced lesions, leading to apoptosis. Similarly, the early expression of XBP1 in ECs promotes ER chaperone expression, while it likely becomes detrimental in advanced lesions. Despite a paucity of evidence in vivo, XBP1 splicing in advanced lesions indicates IRE1α activation, which may promote apoptosis through other nuclease actions. Please see text for specific details