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.
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Unfolded protein response;
ischemic heart disease;
pathological cardiac remodeling
Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Appeared or available online: June 11, 2019