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Curr Top Med Chem. 2019 May 20. doi: 10.2174/1568026619666190521093049. [Epub ahead of print]

Unfolded Protein Response as a Therapeutic Target in Cardiovascular Disease.

Author information

1
Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. United States.
2
Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. United States.

Abstract

Cardiovascular disease is the leading cause of death worldwide. Despite extensive socioeconomic interests and mounting clinical needs, our understanding of the underlying pathophysiology remains incomplete. Multiple forms of the cardiovascular disease involve 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 and misfolded proteins in the endoplasmic reticulum (ER) causes activation of the three signaling branches of the UPR, which otherwise remain quiescent. This ER stress response then transiently lowers global protein translation, augments production of protein chaperones, and enhances ER associated protein degradation with an aim to restore cellular homeostasis. Ample evidence has firmly established that the UPR is strongly induced in heart disease. Recently, the mechanism 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 treatment perspectives.

KEYWORDS:

ATF6; GRP78; IRE1; PERK; XBP1s; cardiovascular disease; endoplasmic reticulum; ischemic heart disease; pathological cardiac remodeling; unfolded protein response

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