Unfolded Protein Response as a Therapeutic Target in Cardiovascular Disease

Author(s): Guangyu Zhang, Xiaoding Wang, Thomas G. Gillette, Yingfeng Deng, Zhao V. Wang*.

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 21 , 2019

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Graphical Abstract:


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

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VOLUME: 19
ISSUE: 21
Year: 2019
Page: [1902 - 1917]
Pages: 16
DOI: 10.2174/1568026619666190521093049
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