Unfolded Protein Response as a Therapeutic Target in Cardiovascular Disease

Guangyu Zhang, Xiaoding Wang, Thomas G. Gillette, Yingfeng Deng, Zhao V. Wang

Research output: Contribution to journalReview article

Abstract

Cardiovascular disease is the leading cause of death worldwide. Despite overwhelming socioeconomic impact and mounting clinical needs, our understanding of the underlying pathophysiology remains incomplete. Multiple forms of cardiovascular disease involve an acute or chronic disturbance in cardiac myocytes, which may lead to potent activation of the Unfolded Protein Response (UPR), a cellular adaptive reaction to accommodate protein-folding stress. Accumulation of unfolded or misfolded proteins in the Endoplasmic Reticulum (ER) elicits three signaling branches of the UPR, which otherwise remain quiescent. This ER stress response then transiently suppresses global protein translation, augments production of protein-folding chaperones, and enhances ER-associated protein degradation, with an aim to restore cellular homeostasis. Ample evidence has established that the UPR is strongly induced in heart disease. Recently, the mechanisms of action and multiple pharmacological means to favorably modulate the UPR are emerging to curb the initiation and progression of cardiovascular disease. Here, we review the current understanding of the UPR in cardiovascular disease and discuss existing therapeutic explorations and future directions.

Original languageEnglish (US)
Pages (from-to)1902-1917
Number of pages16
JournalCurrent topics in medicinal chemistry
Volume19
Issue number21
DOIs
StatePublished - Jan 1 2019

Fingerprint

Unfolded Protein Response
Cardiovascular Diseases
Protein Folding
Molecular Mechanisms of Pharmacological Action
Endoplasmic Reticulum-Associated Degradation
Therapeutics
Endoplasmic Reticulum Stress
Protein Biosynthesis
Cardiac Myocytes
Endoplasmic Reticulum
Proteolysis
Cause of Death
Heart Diseases
Homeostasis
Proteins

Keywords

  • ATF6
  • cardiovascular disease
  • endoplasmic reticulum
  • GRP78
  • IRE1
  • ischemic heart disease
  • pathological cardiac remodeling.
  • PERK
  • Unfolded protein response
  • XBP1s

ASJC Scopus subject areas

  • Drug Discovery

Cite this

Unfolded Protein Response as a Therapeutic Target in Cardiovascular Disease. / Zhang, Guangyu; Wang, Xiaoding; Gillette, Thomas G.; Deng, Yingfeng; Wang, Zhao V.

In: Current topics in medicinal chemistry, Vol. 19, No. 21, 01.01.2019, p. 1902-1917.

Research output: Contribution to journalReview article

Zhang, Guangyu ; Wang, Xiaoding ; Gillette, Thomas G. ; Deng, Yingfeng ; Wang, Zhao V. / Unfolded Protein Response as a Therapeutic Target in Cardiovascular Disease. In: Current topics in medicinal chemistry. 2019 ; Vol. 19, No. 21. pp. 1902-1917.
@article{a7f53f9b4cb44a7f8cd7698f88b650fc,
title = "Unfolded Protein Response as a Therapeutic Target in Cardiovascular Disease",
abstract = "Cardiovascular disease is the leading cause of death worldwide. Despite overwhelming socioeconomic impact and mounting clinical needs, our understanding of the underlying pathophysiology remains incomplete. Multiple forms of cardiovascular disease involve an acute or chronic disturbance in cardiac myocytes, which may lead to potent activation of the Unfolded Protein Response (UPR), a cellular adaptive reaction to accommodate protein-folding stress. Accumulation of unfolded or misfolded proteins in the Endoplasmic Reticulum (ER) elicits three signaling branches of the UPR, which otherwise remain quiescent. This ER stress response then transiently suppresses global protein translation, augments production of protein-folding chaperones, and enhances ER-associated protein degradation, with an aim to restore cellular homeostasis. Ample evidence has established that the UPR is strongly induced in heart disease. Recently, the mechanisms of action and multiple pharmacological means to favorably modulate the UPR are emerging to curb the initiation and progression of cardiovascular disease. Here, we review the current understanding of the UPR in cardiovascular disease and discuss existing therapeutic explorations and future directions.",
keywords = "ATF6, cardiovascular disease, endoplasmic reticulum, GRP78, IRE1, ischemic heart disease, pathological cardiac remodeling., PERK, Unfolded protein response, XBP1s",
author = "Guangyu Zhang and Xiaoding Wang and Gillette, {Thomas G.} and Yingfeng Deng and Wang, {Zhao V.}",
year = "2019",
month = "1",
day = "1",
doi = "10.2174/1568026619666190521093049",
language = "English (US)",
volume = "19",
pages = "1902--1917",
journal = "Current Topics in Medicinal Chemistry",
issn = "1568-0266",
publisher = "Bentham Science Publishers B.V.",
number = "21",

}

TY - JOUR

T1 - Unfolded Protein Response as a Therapeutic Target in Cardiovascular Disease

AU - Zhang, Guangyu

AU - Wang, Xiaoding

AU - Gillette, Thomas G.

AU - Deng, Yingfeng

AU - Wang, Zhao V.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Cardiovascular disease is the leading cause of death worldwide. Despite overwhelming socioeconomic impact and mounting clinical needs, our understanding of the underlying pathophysiology remains incomplete. Multiple forms of cardiovascular disease involve an acute or chronic disturbance in cardiac myocytes, which may lead to potent activation of the Unfolded Protein Response (UPR), a cellular adaptive reaction to accommodate protein-folding stress. Accumulation of unfolded or misfolded proteins in the Endoplasmic Reticulum (ER) elicits three signaling branches of the UPR, which otherwise remain quiescent. This ER stress response then transiently suppresses global protein translation, augments production of protein-folding chaperones, and enhances ER-associated protein degradation, with an aim to restore cellular homeostasis. Ample evidence has established that the UPR is strongly induced in heart disease. Recently, the mechanisms of action and multiple pharmacological means to favorably modulate the UPR are emerging to curb the initiation and progression of cardiovascular disease. Here, we review the current understanding of the UPR in cardiovascular disease and discuss existing therapeutic explorations and future directions.

AB - Cardiovascular disease is the leading cause of death worldwide. Despite overwhelming socioeconomic impact and mounting clinical needs, our understanding of the underlying pathophysiology remains incomplete. Multiple forms of cardiovascular disease involve an acute or chronic disturbance in cardiac myocytes, which may lead to potent activation of the Unfolded Protein Response (UPR), a cellular adaptive reaction to accommodate protein-folding stress. Accumulation of unfolded or misfolded proteins in the Endoplasmic Reticulum (ER) elicits three signaling branches of the UPR, which otherwise remain quiescent. This ER stress response then transiently suppresses global protein translation, augments production of protein-folding chaperones, and enhances ER-associated protein degradation, with an aim to restore cellular homeostasis. Ample evidence has established that the UPR is strongly induced in heart disease. Recently, the mechanisms of action and multiple pharmacological means to favorably modulate the UPR are emerging to curb the initiation and progression of cardiovascular disease. Here, we review the current understanding of the UPR in cardiovascular disease and discuss existing therapeutic explorations and future directions.

KW - ATF6

KW - cardiovascular disease

KW - endoplasmic reticulum

KW - GRP78

KW - IRE1

KW - ischemic heart disease

KW - pathological cardiac remodeling.

KW - PERK

KW - Unfolded protein response

KW - XBP1s

UR - http://www.scopus.com/inward/record.url?scp=85074675219&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074675219&partnerID=8YFLogxK

U2 - 10.2174/1568026619666190521093049

DO - 10.2174/1568026619666190521093049

M3 - Review article

C2 - 31109279

AN - SCOPUS:85074675219

VL - 19

SP - 1902

EP - 1917

JO - Current Topics in Medicinal Chemistry

JF - Current Topics in Medicinal Chemistry

SN - 1568-0266

IS - 21

ER -