Biased β2‐adrenoceptor signalling in heart failure: pathophysiology and drug discovery

Anthony Yiu‐Ho Woo; Ying Song; Rui‐Ping Xiao; Weizhong Zhu

doi:10.1111/bph.12965

journal article Dec 17, 2014

Biased β2‐adrenoceptor signalling in heart failure: pathophysiology and drug discovery

Anthony Yiu‐Ho Woo Ying Song Rui‐Ping Xiao Weizhong Zhu

British Journal of Pharmacology Vol. 172 No. 23 pp. 5444-5456 · Wiley

View at Publisher Save 10.1111/bph.12965

Abstract

The body is constantly faced with a dynamic requirement for blood flow. The heart is able to respond to these changing needs by adjusting cardiac output based on cues emitted by circulating catecholamine levels. Cardiac β‐adrenoceptors transduce the signal produced by catecholamine stimulation viaGsproteins to their downstream effectors to increase heart contractility. During heart failure, cardiac output is insufficient to meet the needs of the body; catecholamine levels are high and β‐adrenoceptors become hyperstimulated. The hyperstimulated β1‐adrenoceptors induce a cardiotoxic effect, which could be counteracted by the cardioprotective effect of β2‐adrenoceptor‐mediatedGisignalling. However, β2‐adrenoceptor‐Gisignalling negates the stimulatory effect of theGssignalling on cardiomyocyte contraction and further exacerbates cardiodepression. Here, further to the localization of β1‐ and β2‐adrenoceptors and β2‐adrenoceptor‐mediated β‐arrestin signalling in cardiomyocytes, we discuss features of the dysregulation of β‐adrenoceptor subtype signalling in the failing heart, and conclude thatGi‐biased β2‐adrenoceptor signalling is a pathogenic pathway in heart failure that plays a crucial role in cardiac remodelling. In contrast, β2‐adrenoceptor‐Gssignalling increases cardiomyocyte contractility without causing cardiotoxicity. Finally, we discuss a novel therapeutic approach for heart failure using aGs‐biased β2‐adrenoceptor agonist and a β1‐adrenoceptor antagonist in combination. This combination treatment normalizes the β‐adrenoceptor subtype signalling in the failing heart and produces therapeutic effects that outperform traditional heart failure therapies in animal models. The present review illustrates how the concept of biased signalling can be applied to increase our understanding of the pathophysiology of diseases and in the development of novel therapies.Linked ArticlesThis article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visithttp://dx.doi.org/10.1111/bph.2015.172.issue-23

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Details

Published: Dec 17, 2014
Vol/Issue: 172(23)
Pages: 5444-5456
License: View

Authors

A

Anthony Yiu‐Ho Woo

Institute of Molecular Medicine Centre for Life Sciences Peking University Beijing China; Key Laboratory of Chemical Genomics School of Chemical Biology and Biotechnology Peking University Shenzhen Graduate School Shenzhen China

Y

Ying Song

Institute of Molecular Medicine Centre for Life Sciences Peking University Beijing China

R

Rui‐Ping Xiao

Institute of Molecular Medicine Centre for Life Sciences Peking University Beijing China; Beijing Key Laboratory of Cardiometabolic Molecular Medicine Peking University Beijing China

W

Weizhong Zhu

Department of Pharmacology Nantong University School of Pharmacy Nantong China

Funding

National Natural Science Foundation of China Award: 31221002

National Basic Research Program of China Award: 2012CB518000

National Science and Technology Major Project of China Award: 2013ZX09508104

National Major Scientific Research Program of China Award: 2012CB910402

Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University

Cite This Article

Anthony Yiu‐Ho Woo, Ying Song, Rui‐Ping Xiao, et al. (2014). Biased β2‐adrenoceptor signalling in heart failure: pathophysiology and drug discovery. British Journal of Pharmacology, 172(23), 5444-5456. https://doi.org/10.1111/bph.12965

Biased β2‐adrenoceptor signalling in heart failure: pathophysiology and drug discovery

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