TY - JOUR
T1 - Therapeutic targets for treatment of heart failure
T2 - Focus on GRKs and β-arrestins affecting βaR signaling
AU - Mangmool, Supachoke
AU - Parichatikanond, Warisara
AU - Kurose, Hitoshi
N1 - Funding Information:
This work was supported in part by grants from JSPS KAKENHI Grant No. JP17H01525 and the National Research Foundation of Korea (NRF) grants funded by the Korea Government (MSIP; 2017K1A1A2004511; to HK), and Thailand Research Fund (Grant RSA6080061; to SM).
Publisher Copyright:
© 2007 - 2018 Frontiers Media S.A. All Rights Reserved.
PY - 2018/11/27
Y1 - 2018/11/27
N2 - Heart failure (HF) is a heart disease that is classified into two main types: HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Both types of HF lead to significant risk of mortality and morbidity. Pharmacological treatment with β-adrenergic receptor (βAR) antagonists (also called β-blockers) has been shown to reduce the overall hospitalization and mortality rates and improve the clinical outcomes in HF patients with HFrEF but not HFpEF. Although, the survival rate of patients suffering from HF continues to drop, the management of HF still faces several limitations and discrepancies highlighting the need to develop new treatment strategies. Overstimulation of the sympathetic nervous system is an adaptive neurohormonal response to acute myocardial injury and heart damage, whereas prolonged exposure to catecholamines causes defects in βAR regulation, including a reduction in the amount of βARs and an increase in βAR desensitization due to the upregulation of G protein-coupled receptor kinases (GRKs) in the heart, contributing in turn to the progression of HF. Several studies show that myocardial GRK2 activity and expression are raised in the failing heart. Furthermore, β-arrestins play a pivotal role in βAR desensitization and, interestingly, can mediate their own signal transduction without any G protein-dependent pathway involved. In this review, we provide new insight into the role of GRKs and β-arrestins on how they affect βAR signaling regarding the molecular and cellular pathophysiology of HF. Additionally, we discuss the therapeutic potential of targeting GRKs and β-arrestins for the treatment of HF.
AB - Heart failure (HF) is a heart disease that is classified into two main types: HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Both types of HF lead to significant risk of mortality and morbidity. Pharmacological treatment with β-adrenergic receptor (βAR) antagonists (also called β-blockers) has been shown to reduce the overall hospitalization and mortality rates and improve the clinical outcomes in HF patients with HFrEF but not HFpEF. Although, the survival rate of patients suffering from HF continues to drop, the management of HF still faces several limitations and discrepancies highlighting the need to develop new treatment strategies. Overstimulation of the sympathetic nervous system is an adaptive neurohormonal response to acute myocardial injury and heart damage, whereas prolonged exposure to catecholamines causes defects in βAR regulation, including a reduction in the amount of βARs and an increase in βAR desensitization due to the upregulation of G protein-coupled receptor kinases (GRKs) in the heart, contributing in turn to the progression of HF. Several studies show that myocardial GRK2 activity and expression are raised in the failing heart. Furthermore, β-arrestins play a pivotal role in βAR desensitization and, interestingly, can mediate their own signal transduction without any G protein-dependent pathway involved. In this review, we provide new insight into the role of GRKs and β-arrestins on how they affect βAR signaling regarding the molecular and cellular pathophysiology of HF. Additionally, we discuss the therapeutic potential of targeting GRKs and β-arrestins for the treatment of HF.
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U2 - 10.3389/fphar.2018.01336
DO - 10.3389/fphar.2018.01336
M3 - Review article
AN - SCOPUS:85057873264
VL - 9
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
SN - 1663-9812
IS - NOV
M1 - 1336
ER -