Beta3-Adrenoreceptors in Cardiovasular Diseases: New Roles for an "Old" Receptor

Beta3-adrenoreceptors (B3AR) are traditionally known as metabolic receptors in adipose tissue, but came into focus in the cardiovascular field after our demonstration of their expression in human cardiac myocytes and endothelial cells, where they mediate endothelium-dependent relaxation of coronary resistance vessels through production of both nitric oxide and endothelium-dependent hyperpolarization factor(s) (EDHF). B3AR are also expressed at the plasma membrane of rodent and human cardiac myocytes. Notably, their expression is increased in several forms of human cardiomyopathies, which raises questions about their adaptive or maladaptive role in myocardial remodelling. To test the hypothesis that they may counteract the adverse effect of B1-B2-AR overactivation, we set out to study the cardiac phenotype of transgenic mice expressing human recombinant B3AR under the cardiac-specific alpha-MHC promoter. While exhibiting no apparent phenotype at basal state, these mice seem protected from hypertrophic remodeling under a variety of stresses, without developing left ventricular dysfunction. Notably, this protection seems to depend on a functional nitric oxide synthase (NOS), as it is abrogated under NOS inhibition. These features can all be recapitulated in homotypic cardiac myocytes cultures in vitro. B3AR transgenic mice may also be protected from fibrosis through a paracrine cross-talk to cardiac fibroblasts. These data suggest a beneficial role of B3AR in myocardial remodeling through attenuation of fibrosis and of excessive cardiac myocyte hypertrophy, while at the same time optimizing perfusion. As B3AR are resistant to homologous desensitization, they are attractive targets for therapeutic interventions in the setting of chronic sympathetic stimulation, as it is prevalent in heart failure and several cardiomyopathies.