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

Fig. (1).. Endoplasmic Reticulum (ER) stress and the Unfolded Protein Response (UPR).

Under resting conditions, luminal domains of the three transducers of UPR bind ER master chaperone GRP78. ER stress ensues upon accumulation of misfolded and unfolded proteins. GRP78 then interacts with unfolded proteins, leading to activation of the three UPR branches. The initial response attempts to restore normal function by attenuation of protein synthesis and increasing chaperone production. PERK forms dimers and autophosphorylates, leading to downstream phosphorylation of eIF2α and a decrease in global translation. Phosphorylation of eIF2α also induces the translation of ATF4 and downstream targets such as CHOP. ATF6 is activated by site 1 and site 2 proteases (S1P and S2P) in the Golgi and transcriptionally competent nuclear ATF6 (ATF6n) is then translocated into the nucleus. IRE1 undergoes dimerization and autophosphorylation, which results in the cleavage of the XBP1 mRNA to form transcription factor XBP1s.

Fig. (2).. GRP78 as a therapeutic target in cardiovascular disease.

Different therapeutic approaches have been discovered for intervention of GRP78. The main approaches are as the following: (I) Direct activation of GRP78 can relieve neurodegenerative disorders and may be useful for cardiac ischemia/reperfusion injury; (II) Direct inhibition of GRP78 may suppress tumor growth and be useful to treat pathological cardiac remodeling; (III) GRP78 peptide can either directly modulate GRP78 activity or to be used as a precisely targeting vehicle to deliver therapeutic drugs.

Fig. (3).. PERK as a therapeutic target in cardiovascular disease.

The main approaches to manipulate PERK are: (I) Direct activation of PERK can improve neurodegenerative disorders and suppress the development of cancer; (II) Direct inhibition of PERK can mitigate tumor growth, prion disease, and cardiac arrhythmia; (III) PERK targeting miRNA may be used to specifically suppress PERK for arrhythmia treatment.

Fig. (4).. ATF6 as a therapeutic target in cardiovascular disease.

Different therapeutic approaches aiming to intervene ATF6 include: (I) Activation of ATF6 may relieve ER stress-related heart disease and stroke; (II) Inhibition of ATF6 may be exploited to treat cancer; (III) AAV9-mediated gene therapy can improve the outcome of cardiac ischemia/reperfusion.

Fig. (5).. IRE1/XBP1s as a therapeutic target in cardiovascular disease.

The main approaches are as the following: (I) Direct activation of IRE1/XBP1s may relieve ER stress-related cardiovascular disease; (II) Inhibition of IRE1/XBP1s can suppress atherosclerosis development; (III) miRNA-mediated gene therapy can be used to improve cardiac dysfunction of heart failure.