Therapeutic targets for treatment of heart failure: Focus on GRKs and β-arrestins affecting βAR signaling
- 1Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Japan
- 2faculty of Pharmacy, Mahidol University, Thailand
Heart failure (HF) is a chronic 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 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 in regard to the molecular and cellular pathophysiology of HF. Additionally, we discuss the therapeutic potential of targeting GRKs and β-arrestins for the treatment of HF.
Keywords: GRK, G-protein receptor kinase, Heart Failure, beta-arrestin, beta-blocker, beta-adrenergic receptor
Received: 17 Aug 2018;
Accepted: 30 Oct 2018.
Edited by:Yuichi Hattori, University of Toyama, Toyama, Japan
Reviewed by:Canan G. Nebigil, Centre national de la recherche scientifique (CNRS), France
Masao Endoh, Yamagata University, Japan
Copyright: © 2018 Kurose, Mangmool and Parichatikanond. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Hitoshi Kurose, Kyushu University, Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Fukuoka, Japan, firstname.lastname@example.org