Seminars in Immunopathology

, Volume 35, Issue 3, pp 321–332 | Cite as

The UPR in atherosclerosis

  • Alex X. Zhou
  • Ira Tabas


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.


Atherosclerosis Unfolded protein response Endoplasmic reticulum Stress 



AMP-activated protein kinase alpha 2


Activator protein 1




Activating transcription factor 6


Brefeldin A


Calcium/calmodulin-dependent protein kinase II




CCAAT/enhancer binding protein homologous protein


Chemokine CXC motif ligand 3


Directional coronary atherectomy


Endothelial cells


Eukaryotic initiation factor 2α


Endoplasmic reticulum


ER-associated degradation


Extracellular signal-regulated kinase


ER oxidase 1α


Free cholesterol


Glucose-regulated protein 78




Heat shock protein 47


Human umbilical vein endothelial cell


IκB kinase




Inositol-requiring protein 1 α


c-Jun-N-terminal kinase


Liver X receptor


Mitogen-activated protein kinases


Macrophage colony-stimulating factor


Nucleotide oligomerization domain receptor protein 3


Oxidized low-density lipoprotein


4-Phenylbutyric acid


Protein kinase RNA-like ER kinase


Protein phospholipase 1, catalytic subunit


Pattern recognition receptors


IRE1-dependent decay


Stable angina pectoris


Smooth muscle cells


Steroid receptor RNA activator 1


Signal transducer and activator of transcription-1


Spliced XBP1 protein


T cell death associated gene 51


Total serum homocysteine


Toll-like receptors


TNFR-associated factor 2


Tumor necrosis factor-α


Tauroursodeoxycholic acid


Thioredoxin-interacting protein


Unfolded protein response


X-box binding protein 1


Unstable angina pectoris



A.X.Z. is supported by the Swedish Research Council. I.T. is supported by NIH grants. The authors gratefully acknowledge the members of the Tabas laboratory who contributed to the studies described herein. We also thank Dr. Christopher M. Scull for his helpful discussions and valuable comments.


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© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of MedicineColumbia UniversityNew YorkUSA

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