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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 via Gs proteins 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-mediated Gi signalling. However, β2-adrenoceptor-Gi signalling negates the stimulatory effect of the Gs signalling 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 that Gi-biased β2-adrenoceptor signalling is a pathogenic pathway in heart failure that plays a crucial role in cardiac remodelling. In contrast, β2-adrenoceptor-Gs signalling increases cardiomyocyte contractility without causing cardiotoxicity. Finally, we discuss a novel therapeutic approach for heart failure using a Gs-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.
Woo et al. (Thu,) studied this question.