Targeting β(3)-Adrenergic Receptors in the Heart: Selective Agonism and β-Blockade

Cardiac diseases, such as heart failure, remain leading causes of morbidity and mortality worldwide, with myocardial infarction as the most common etiology. HF is characterized by β-adrenergic receptor (βAR) dysregulation that is primarily due to the upregulation of G protein–coupled receptor kinases that leads to overdesensitization of β(1) and β(2)ARs, and this clinically manifests as a loss of inotropic reserve. Interestingly, the “minor” βAR isoform, the β(3)AR, found in the heart, lacks G protein–coupled receptor kinases recognition sites, and is not subject to desensitization, and as a consequence of this, in human failing myocardium, the levels of this receptor remain unchanged or are even increased. In different preclinical studies, it has been shown that β(3)ARs can activate different signaling pathways that can protect the heart. The clinical relevance of this is also supported by the effects of β-blockers which are well known for their proangiogenic and cardioprotective effects, and data are emerging showing that these are mediated, at least in part, by enhancement of β(3)AR activity. In this regard, targeting of β(3)ARs could represent a novel potential strategy to improve cardiac metabolism, function, and remodeling.