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.
N1 - Funding Information:
This work was supported by grants from the American Heart Association (14SDG18440002 to ZVW, 17IRG3346-0191 to ZVW), American Diabetes Association (1-17-IBS-120 to ZVW), and NIH (R01-HL137723 to ZVW).
Publisher Copyright:
© 2019 Bentham Science Publishers.
PY - 2019
Y1 - 2019
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 mis-folded 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 mis-folded 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 - PERK
KW - Pathological cardiac remodeling
KW - Unfolded protein response
KW - XBP1s
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U2 - 10.2174/1568026619666190521093049
DO - 10.2174/1568026619666190521093049
M3 - Review article
C2 - 31109279
AN - SCOPUS:85074675219
SN - 1568-0266
VL - 19
SP - 1902
EP - 1917
JO - Current topics in medicinal chemistry
JF - Current topics in medicinal chemistry
IS - 21
ER -