Emerging role of IRE1α in vascular diseases

Abstract

A mounting body of evidence suggests that the endoplasmic reticulum stress and the unfolded protein response are involved in the underlying mechanisms responsible for vascular diseases. Inositol-requiring protein 1α (IRE1α), the most ancient branch among the UPR-related signaling pathways, can possess both serine/threonine kinase and endoribonuclease (RNase) activity and can perform physiological and pathological functions. The IRE1α-signaling pathway plays a critical role in the pathology of various vascular diseases. In this review, we provide a general overview of the physiological function of IRE1α and its pathophysiological role in vascular diseases.

Keywords: IRE1α; XBP1; atherosclerosis; vascular disease.

FIGURE 1

The structure of IRE1α. IRE1α consist of two domains: the endoplasmic reticulum luminal domain, and serine/threonine kinase and endoribonuclease (RNase) domains. In resting conditions, IRE1α binds to Bip/GRP78. Upon stress, IRE1α disintegrates with Bip/GRP78 and activated via autophosphorylation and dimerization/oligomerization.

FIGURE 2

The IRE1α‐signaling pathway. The active RNase cleaves 26 nucleotides from unspliced form of XBP1 (XBP1u) mRNA and produce the spliced form of XBP1 (XBP1s) mRNA. XBP1s is a crucial transcription factor, which could translocate into the nucleus and initiate the transcriptional process. IRE1α also cleaves a subset of ER‐associated mRNAs. IRE1α activates several signaling pathways through inflammation, apoptosis, and autophagy. ASK1, apoptosis‐signaling kinase 1; CHOP, C/EBP‐homologous protein; FOXO1, Forkhead box O1; IKK, IκB kinase; JNK, c‐Jun NH2‐terminal kinase; LD, luminal domain; MANF, mesencephalic astrocyte‐derived neurotrophic factor; NF‐κB, nuclear factor‐kappa B; RIDD, regulated IRE1‐dependent decay; TRAF2, tumor necrosis factor receptor associated factor 2; XBP1s, spliced form of X‐box binding protein‐1; and XBP1u, unspliced form of X‐box binding protein‐1.

FIGURE 3

Mechanisms of IRE1α in endothelial cells (ECs) in atherosclerosis. IRE1α can be activated in ECs treated with risk factors for atherosclerosis, including oxidized low‐density lipoprotein, homocysteine, high glucose, shear stress, arsenite, and disturbed flow. IRE1α participates in the progression of atherosclerosis through inflammation, apoptosis, and autophagy. ACE, angiotensin‐converting enzyme; AGT, angiotensinogen; ASK1, apoptosis‐signaling kinase 1; AT1R, angiotensin II type 1 receptor; HIF1α, hypoxia inducible factor 1α; IRF1, interferon regulatory factor 1; IKK, IκB kinase; JNK, c‐Jun NH2‐terminal kinase; NF‐κB, nuclear factor‐kappa B; ox‐LDL, oxidized low‐density lipoprotein; TRAF2, tumor necrosis factor receptor associated factor 2; VCAM‐1, vascular cell adhesion molecule‐1; XBP1s, spliced form of X‐box binding protein‐1; and XBP1u, unspliced form of X‐box binding protein‐1.

FIGURE 4

Mechanisms of IRE1α in macrophages in atherosclerosis. IRE1α can be activated in macrophages treated with oxidized low‐density lipoprotein and angiotensin II. IRE1α participates in the progression of atherosclerosis through inflammation, apoptosis, and autophagy. IRE1 kinase activation induces Fragile X Mental Retardation protein (FMRP) phosphorylation, and suppresses the macrophage cholesterol efflux and efferocytosis. IRE1α also promotes oxLDL uptaking through CD36. ASK1, apoptosis‐signaling kinase 1; FMRP, Fragile X Mental Retardation protein; JNK, c‐Jun NH2‐terminal kinase; ox‐LDL, oxidized low‐density lipoprotein; TRAF2, tumor necrosis factor receptor associated factor 2; XBP1s, spliced form of X‐box binding protein‐1; and XBP1u, unspliced form of X‐box binding protein‐1.