Reviews
This Review is the Introduction of a thematic series on Endoplasmic Reticulum Stress and Cardiac Diseases, which
includes the following articles:
What Is the Role of ER Stress in the Heart? Introduction and Series Overview
Biology of ER Stress in the Heart
ER Stress and Cardiac Hypertrophy/Heart Failure
ER Stress, Atherosclerosis, and Coronary Plaque Rupture
Therapeutic Targets of ER Stress in Cardiovascular Diseases
Masafumi Kitakaze, Guest Editor
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What Is the Role of ER Stress in the Heart?
Introduction and Series Overview
Masafumi Kitakaze, Osamu Tsukamoto
T
hree decades ago, investigators studying the function
of the endoplasmic reticulum (ER) focused on its role
in transiently regulating Ca2⫹ concentrations in cardiovascular cells. Muscle cells, including cardiomyocytes, contain a specialized smooth ER, the sarcoplasmic reticulum,
and Ca2⫹ release and reuptake by the sarcoplasmic reticulum trigger the contraction and relaxation of the myofibrils, respectively. Cardiovascular research has been focused on many aspects of muscle physiology, including
myocardial contractility and relaxation, to better understand the regulation of systemic and cardiac hemodynamics. Furthermore, accumulating evidence indicates that
perturbation in Ca2⫹ homeostasis contributes to cardiovascular disease and is an effective therapeutic target for the
treatment of heart disease. While intracellular Ca2⫹ homeostasis was being investigated in great detail, a major
discovery in ER biology was made in 1988, with the first
description of the ER-stress response.1 Although cardiovascular researchers did not initially enter this field, there
has been a large shift in cardiovascular research toward
this topic over the past several years.
To assess the significance of these findings, we must
consider the functions of the ER. Cellular homeostasis and
function require properly folded proteins. Protein folding
is the process by which a linear polymer of amino acids
acquires a unique 3D structure (the native conformation)
capable of performing its cellular function(s). During the
folding process, proteins often interact with molecular
chaperones that bind to the hydrophobic regions of unfolded or incompletely folded proteins to facilitate proper
folding but, perhaps more importantly, prevent the accumulation of misfolded proteins in toxic aggregates. Throughout their lifetime, cells are exposed to a range of environmental
stressors, such as radiation, hypoxia, heat, osmotic shifts, and
oxidation, and all of these can lead to the adoption of aberrant
3D structures in damaged proteins.2 Cells carefully monitor
for the presence of misfolded proteins in different compartments. The accumulation of misfolded proteins in the cytosol
triggers a heat-shock response, which stimulates the transcription of genes encoding cytosolic chaperones to refold destabilized proteins. Similarly, the accumulation of misfolded proteins
in the ER initiates a signaling cascade from the ER to the nucleus
that induces a comprehensive gene expression program to
increase the protein folding capacity of the cell according to
need.3 However, the mechanism and pathways that are essential
for the ER to nucleus signaling were entirely unknown for quite
some time.
Since the first description of the ER stress response, the
contributions of many scientists have come to define the unfolded protein response (UPR), and it is now widely accepted
Original received April 26, 2010; revision received May 6, 2010; accepted May 12, 2010. In April 2010, the average time from submission to first
decision for all original research papers submitted to Circulation Research was 15.2 days.
From the Department of Cardiovascular Medicine (M.K.), National Cardiovascular Center, Suita; Department of Molecular Cardiology (O.T.), Osaka
University Graduate School of Medicine, Suita, Japan.
Correspondence to Masafumi Kitakaze, MD, PhD, Department of Cardiovascular Medicine, National Cardiovascular Center, Suita, Osaka 565-8565,
Japan. E-mail [email protected]
(Circ Res. 2010;107:15-18.)
© 2010 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/CIRCRESAHA.110.222919
15
16
Circulation Research
July 9, 2010
Non-standard Abbreviations and Acronyms
CHOP
Bip/GRP
ER
ERp
UPR
CCAAT/enhancer binding protein (C/EBP) homologous protein
binding protein/glucose-regulated protein
endoplasmic reticulum
endoplasmic reticulum protein
unfolded protein response
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that an imbalance between the delivery of unfolded proteins to
the ER and the capacity of the cellular folding machinery leads
to ER stress.4 The ER has both smooth and rough regions. The
rough ER forms stacks of flattened cisternae and is composed of
a membrane-enclosed lumen. The smooth ER membrane is
connected to these cisternae and forms a fine network of tubules.
The smooth ER is the principal site of lipid synthesis and
modification in specialized cells, including steroid hormone–
secreting cells and hepatocytes. In contrast, the synthesis, modification, folding, and processing of nascent polypeptide chains
of secreted, transmembrane, and luminal proteins occur in the
rough ER. The presence of ribosomes on the cytosolic face of
the ER gives rise to the rough ER, and ribosomes bind a single
mRNA molecule and initiate protein synthesis. For nearly all
proteins in the secretory pathway, a specific signal sequence is
recognized by transmembrane proteins in the ER, and nascent
polypeptides are then translocated across the ER membrane and
become membrane imbedded or are released into the ER lumen.
Within the ER, a number of different chaperones, including
binding protein/glucose regulated protein (BiP/GRP)78, GRP94,
calnexin, and calreticulin; and oxidoreductases, such as protein
disulfide isomerase, ER protein (ERp)57, and ERp72, coordinately act to promote protein folding.5 BiP/GRP78 is a homolog
of heat shock protein 70, and GRP94 is a homolog of heat shock
protein 90. Calnexin, calreticulin, and ERp57 specifically act on
N-glycosylated proteins.
What is the UPR? The UPR was first studied in animal
cells, where the expression of BiP/GRP78, GRP94, protein
disulfide isomerase, ERp57, and/or ERp72 is induced by
several different cellular stressors that lead to the accumulation of unfolded proteins in the ER.1,6 Additionally, the
UPR is also active in unicellular organism such as the
yeast Saccharomyces cerevisiae,7,8 and many of the proteins involved in the UPR are conserved across these
diverse organisms, strongly indicating the importance of the
ER protein folding machinery for cell survival. Despite this
degree of conservation, higher eukaryotic organisms have
evolved a more complex 3-pronged UPR signaling pathway
involving PERK (pancreatic ER kinase), IRE1 (inositolrequiring transmembrane kinase/endonuclease 1), and ATF6
(activating transcription factor 6), whereas the pathway in
yeast is linear involving only IRE1.9
Our understanding of the cellular response to ER stress has
dramatically increased over the past decade.4 Recently, a
novel cell-specific ER stress transducer10 and a cell type–
specific response to ER stress11 have been discovered. The
body of all higher animals is composed of heterogenous
tissues and cells that are exposed to different cellular stressors
in a tissue-specific manner, and this may contribute to the
acquisition of specific morphology and function. These variations can extend to the ER. Cellular ER content and
properties differ between cell types to accommodate specialized cellular functions. For example, highly differentiated
cells that secrete large amounts of protein, such as exocrine
acinar cells and plasma cells, have more extensive and
better-developed rough ER than nonsecretory cells. Furthermore, the morphology and function of the rough ER can
change in the same cell in response to a changing cellular
environment. Stressed hypertrophic cardiomyocytes develop
a more extensive rough ER than nonstressed cardiomyocytes.12 The sensitivity of cells to ER stress also varies. When
cardiomyocytes and cardiac fibroblasts are exposed to the
same degree of ER stress, the cells respond differently with
respect to transcriptional activity and apoptosis, and similar
phenomena have been observed in the nervous system which
is composed of different cell types such as neuronal and glial
cells.13 Thus, it is possible that cell- or organ-specific ER
stress responses may take place, and future studies should
focus on the specificity of the ER stress signaling and/or
responses.
The role of UPR is among the most important areas of
ongoing investigation into the pathogenesis of different disease states. Abnormalities in the UPR have been implicated in
several diseases, including neurodegenerative diseases,14,15
bipolar disorder,16 and both type 117,18 and type 2 diabetes
mellitus.19,20 Many lines of evidence indicate that the UPR
and ER stress play an important role in the development of
cardiovascular diseases. UPR activation is seen in both hypertrophic and failing hearts. Indeed, several studies suggest that the
increased expression of CHOP (CCAAT/enhancer binding protein [C/EBP] homologous protein), a component of the ERinitiated apoptotic signaling pathway, may be involved in the
transition from cardiac hypertrophy to heart failure.12,21 Additionally, an association between altered Ca2⫹ handling, a common finding in patients with failing hearts, and UPR activation
has also been reported.22
The UPR is also activated in ischemic myocardium23,24
and the ER-initiated apoptotic signaling molecules, such as
CHOP and caspase 12, may contribute to cardiomyocyte
death after hypoxic insult.25 The UPR is also activated in
atherosclerotic lesions, and ER-initiated apoptotic signaling could contribute to plaque instability by inducing
apoptosis in macrophages and smooth muscle cells.26 –28
Atherosclerotic plaques are surrounded by potential
sources of ER stress such as oxidized lipids, reactive
oxygen species, metabolic stressors, and hypoxia. However, despite accumulating evidence documenting the crucial role of ER stress in the development of cardiovascular
diseases, there is still much to learn about what could
constitute an essential pathway in the pathogenesis of these
disorders. In addition to its role in disease pathogenesis,
the UPR may act as a protective response early during cell
injury, but prolonged UPR activation is deleterious, leading to disturbed calcium homeostasis, increased protein
accumulation, loss of ER function, and the death.
Kitakaze and Tsukamoto
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ER stress has recently become a potential target for new
drug discovery in oncology,29 and in cardiomyocytes, supplemental and/or pharmacological induction of GRP78 has been
shown to attenuate ER stress–induced cell death.30 In addition, it has been reported that chemical ER chaperones can
reduce ER stress,31 suggesting that small molecules can affect
ER stress signaling in disease states. Given the possible
development of novel UPR-targeted therapies for cardiovascular diseases, it is essential to know which components of
the ER stress response to target and which particular disease
stage will be most amenable to therapy.
This series contains reviews describing the present
thinking about the role of ER stress in cardiovascular
physiology and disease, as well as its potential therapeutic
implications. A full understanding of the protein quality
control network in the ER is becoming clearer, and the
UPR and ER stress response are at the center of this
network. This paradigm has evolved from the discovery in
late 1980s that the accumulation of misfolded proteins in
the ER initiates signaling to the nucleus to adjust the
protein-folding capacity of the cell.
In this series, Marek Michalak, a recognized leader in the
molecular biology of the ER, will provide an overview of the
biology of ER stress with a focus on the heart. Cardiac
hypertrophy and heart failure are common features of cardiovascular disease, and coronary artery diseases, including atherosclerosis, are the most prevalent cause of cardiac deaths worldwide. Accordingly, Rick Austin and Ira Tabas review the role of
ER stress in cardiac tissues and coronary arteries, in both health
and disease. Finally, we will discuss the molecular and pharmacological strategies that are needed to modulate ER stress for
preventing cardiovascular diseases. Studies on the role of ER
stress in cardiovascular disease are entering a new and exciting
phase, and this review series promises to provide valuable
insights into this emergent field of research.
Sources of Funding
This work was supported by Grants-in-Aid from the Ministry of
Health, Labor, and Welfare (Japan); the Ministry of Education,
Culture, Sports, Science, and Technology (Japan); the Japan Heart
Foundation; and the Japan Cardiovascular Research Foundation.
Disclosures
The authors have no conflict of interests to disclose.
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ER Stress Series Introduction and Overview
17
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KEY WORDS: ER stress
disease
䡲
UPR
䡲
protein quality control
䡲
cardiovascular
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What Is the Role of ER Stress in the Heart?: Introduction and Series Overview
Masafumi Kitakaze and Osamu Tsukamoto
Downloaded from http://circres.ahajournals.org/ by guest on June 15, 2017
Circ Res. 2010;107:15-18
doi: 10.1161/CIRCRESAHA.110.222919
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