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

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 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. LINKED ARTICLES IntroductionCardiovascular disease is the number one cause of death globally (World Health Organization, 2011). Coronary artery disease is the most prevalent form of cardiovascular disease and is the cause of heart attack (myocardial infarction), an acute illness with very high mortality and morbidity. Given that adult cardiomyocytes cannot re-enter the cell cycle, the death of cardiomyocytes as a result of the blockade of a major coronary artery will permanently weaken cardiac performance. The workload of the remaining cardiomyocytes has to increase to maintain a sufficient cardiac output. A series of compensatory responses are usually triggered, which in many cases lead to structural changes in the heart itself. The process once started will progress to a serious chronic illness called heart failure (HF). Thus, survivors of heart attacks are predisposed to HF, a potentially fatal condition manifested by a progressive decline of cardiac function. HF is also a common converging point of various late-stage cardiovascular conditions, such as cardiomyopathy, valvular heart disease and hypertension. Age is an important risk factor for ...

Adrenergic Receptors in Individual Ventricular Myocytes

“…Contrary to current models, 1,2 we find that the β1 and β2 are not the predominant myocyte ARs. Instead, the dominant myocyte ARs are the β1 and the α1B, which are present in all cells.…”

“…Also surprising, we find no prior reports of β-AR binding in β1/2-KO hearts or myocytes, to quantify the β3. We find that the β3 is far more abundant in heart than is appreciated currently, 1,2,5 comprising about 20% of total β-ARs (Figure 6), most likely in endothelial cells (Online Figure V). 27 …”

“…The β1 and β2 are considered the most important cardiac ARs, with a minor role for α1 and β3. 1,2 β-ARs control the rate and strength of cardiac contraction. The role of the α1B might be cardiac growth, 3 and the β2, β3, and α1A are each implicated in cardioprotection.…”

The influence of adrenaline on contractility and excitability of myocardium of rat right ventricle depending on phases of the estrous cycle and pregnancy

“…Нами подтверждены данные о способности адреналина оказывать положи-тельный инотропный эффект в опытах с полосками миокарда крысы [36,[43][44][45][46], в том числе миокарда правого желудочка крыс [36,47]. При этом впервые показано, что у небеременных крыс (независимо от фазы эстрального цикла), а также у крыс на ранних сроках беременности положительный инотропный эффект адреналина в определенной степени зависит от его концентраций (это особенно характерно для ранних сроков беременности) и достигает максимальных значений при кон-центрации 10 -5 г/мл.…”

A New Pathway for Sympathetic Cardioprotection in Heart Failure

“…22 A body of evidence suggests cardioprotection by the β2-AR, possibly via a Gi, G βγ, PI3K, Akt pathway, 23 or alternately via a Gs mechanism. 24 However, some data argue against β2-mediated cardioprotection. 25 β3-AR activation can protect the heart from injury via NOS activation.…”