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Cardiovascular Disease and Endoplasmic Reticulum Stress

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Endoplasmic Reticulum Stress in Health and Disease

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Abstract

The endoplasmic reticulum (ER) is an intracellular organelle involved in maintaining protein and ion homeostasis and is vital for preserving cardiovascular health. Within the ER are a number of important proteins involved in sustaining cellular homeostasis, including molecular chaperones, Ca2+ binding proteins, and proteins involved in ER stress sensing and communication with other organelles. When ER homeostasis is disrupted, either by fluctuations in ion concentration or by a buildup of mis-folded protein, ER stress is triggered followed by a specific cellular response termed the Unfolded Protein Response (UPR). A number of conditions trigger ER stress, including hypoxia, ischemia/reperfusion, glucose starvation and several disease states. The UPR has three main effects; cessation of protein synthesis into the ER, up-regulation in expression of ER protein chaperones and up-regulation in ER-associated degradation (ERAD) of mis-folded proteins. The UPR can also trigger apoptosis if the insult is prolonged or severe. The cardiovascular system has recently been linked to ER stress with an ability to protect the heart, but is also observed to be pathologically damaging. Suppression of overall protein synthesis with up-regulation of ER resident molecular chaperones such as calreticulin and BiP/GRP78 may initially resolve the ER stress and restore ER homeostasis, but if ER stress conditions are extenuating, the UPR will stimulate apoptosis, characteristic of ischemia/reperfusion (I/R) injury in the heart. Pressure overload can also trigger ER stress, performing an important role in heart recovery. ER stress is implicated in several disease conditions including I/R of the brain or heart, heart failure and diabetes. UPR can be specifically activated in cardiac tissues by decreases in ATP, ER Ca2+, or UDP-glucose. An increase in UPR components such as ATF6 occurs within 24 hours of myocardial infarction in mice, as well as oxygen, serum and glucose deprivation in rats. As a number of cardiovascular diseases involve ER stress and the UPR, the understanding and management of ER stress and the UPR is of paramount importance.

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Abbreviations

ASK1:

apoptosis signaling kinase 1

ATF4:

activating transcription factor 4

ATF6:

activating transcription factor 6

ATG:

autophagic protein

Bax:

Bcl2 associated X protein

Bcl2:

B-cell CLL/lymphoma 2

BH3:

Bcl-2 homology domain 3

Bid:

BH3 interacting domain death agonist

BiP:

immunoglobulin heavy chain-binding protein

CHOP:

C/EBP-homologous protein

CRE:

cyclic AMP response element

CREB:

cAMP responsive element binding protein

EDEM1:

endoplasmic reticulum degradation enhancer, mannosidase alpha-like 1

eIF2α:

eukaryotic translation initiation factor 2A

Elk1:

ETS domain containing protein

ER:

endoplasmic reticulum

ERAD:

endoplasmic reticulum associated degradation

ERdj3:

endoplasmic reticulum DnaJ homolog 3

ERdj4:

endoplasmic reticulum DnaJ homolog 4

ERK1/2:

extracellular signal-regulated kinases 1 and 2

ERp57:

ER protein 57

ERp72:

endoplasmic reticulum protein 72

ERp59:

ER protein 59

ERSE:

endoplasmic reticulum stress element

GADD34:

growth arrest and DNA damage inducible protein 34

GRP94:

glucose related protein 94

GRP78:

glucose related protein 78

HSP40:

heat shock protein 40

Hyou1:

hypoxia up regulated 1

iNOS:

inducible nitric oxide synthase

Ins3PR:

inositol 3-phosphate receptor

I/R:

ischemia/reperfusion

IRE1:

inositol requiring protein 1

JIK:

c-Jun N-terminal inhibitory kinase

JNK:

c-Jun kinase

MEF2c:

myocyte enhancer factor 2C

MCP1:

monocyte chemotactic protein 1

MCPIP:

MCP1 inhibitory protein

c-Myc:

myelocytomatosis viral oncogene homolog

NFAT:

nuclear factor of activated T-cells

Oasis:

old astrocyte specifically-induced substance

PARM1:

prostatic androgen repressed message 1

P58IPK:

protein kinase inhibitor of 58-kDa

PDIa6:

protein disulfide isomerase family A, member 6

PDI:

protein disulfide isomerase

PERK:

protein kinase RNA-like endoplasmic reticulum kinase

PI3K:

phosphoinositides 3-kinase

RCAN1:

regulator of calcineurin 1

ROS:

reactive oxygen species

S1P:

site 1 protease

S2P:

site 2 protease

SERCA2:

sarco/endoplasmic reticulum Ca2+ ATPase 2

SOD:

superoxide dismutase 1

Stat3:

signal transducer and activator of transcription 3

TRAF2:

tumor necrosis factor receptor associated factor 2

UPR:

unfolded protein response

UPRE:

unfolded protein response element

XBP1:

X-box binding protein 1

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Acknowledgment

Work is our laboratory is supported by grants from the Canadian Institutes of Health Research, and Alberta Innovates-Heath Solutions.

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  1. Department of Biochemistry, University of Alberta, T6G 2H7, Edmonton, Alberta, Canada

    Jody Groenendyk & Marek Michalak

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Correspondence to Marek Michalak .

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  1. Dept Molec Cell Bio, K.U. Leuven, Harestraat/Gasthuisberg, B-3000 Leuven, 3000, Belgium

    Patrizia Agostinis

  2. School of Natural Science, Department of Biochemistry, NUI Galway, University Road, Galway, Ireland

    Samali Afshin

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Groenendyk, J., Michalak, M. (2012). Cardiovascular Disease and Endoplasmic Reticulum Stress. In: Agostinis, P., Afshin, S. (eds) Endoplasmic Reticulum Stress in Health and Disease. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4351-9_15

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