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Seminars in Immunopathology

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

The UPR in atherosclerosis

  • Alex X. Zhou
  • Ira Tabas
Review

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.

Keywords

Atherosclerosis Unfolded protein response Endoplasmic reticulum Stress 

Abbreviations

Ampkα2

AMP-activated protein kinase alpha 2

AP1

Activator protein 1

apoB

Apolipoprotein-B

ATF6

Activating transcription factor 6

BFA

Brefeldin A

CaMKII

Calcium/calmodulin-dependent protein kinase II

CASP2

Caspase-2

CHOP

CCAAT/enhancer binding protein homologous protein

CXCL3

Chemokine CXC motif ligand 3

DCA

Directional coronary atherectomy

ECs

Endothelial cells

eIF2α

Eukaryotic initiation factor 2α

ER

Endoplasmic reticulum

ERAD

ER-associated degradation

ERK

Extracellular signal-regulated kinase

ERO1α

ER oxidase 1α

FC

Free cholesterol

GRP78

Glucose-regulated protein 78

HHcy

Hyperhomocysteinemia

HSP47

Heat shock protein 47

HUVEC

Human umbilical vein endothelial cell

IKK

IκB kinase

IL-6

Interleukin-6

IRE1α

Inositol-requiring protein 1 α

JNK

c-Jun-N-terminal kinase

LXR

Liver X receptor

MAPK

Mitogen-activated protein kinases

M-CSF

Macrophage colony-stimulating factor

NLRP3

Nucleotide oligomerization domain receptor protein 3

oxLDL

Oxidized low-density lipoprotein

PBA

4-Phenylbutyric acid

PERK

Protein kinase RNA-like ER kinase

PP1c

Protein phospholipase 1, catalytic subunit

PRRs

Pattern recognition receptors

RIDD

IRE1-dependent decay

SAP

Stable angina pectoris

SMCs

Smooth muscle cells

SRA1

Steroid receptor RNA activator 1

STAT1

Signal transducer and activator of transcription-1

sXBP1

Spliced XBP1 protein

TDAG51

T cell death associated gene 51

tHcy

Total serum homocysteine

TLRs

Toll-like receptors

TRAF2

TNFR-associated factor 2

TNFα

Tumor necrosis factor-α

TUDCA

Tauroursodeoxycholic acid

TXNIP

Thioredoxin-interacting protein

UPR

Unfolded protein response

XBP1

X-box binding protein 1

UAP

Unstable angina pectoris

Notes

Acknowledgments

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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