Persistent activation of the cardiac β-adrenergic system may contribute to the pathogenesis of congestive heart failure. Both β₁- and β₂-adrenoceptors are known to mediate these noxious effects, yet the β₁-adrenoceptor-PKA axis has received greater attention with less information available on β₂-adrenoceptor driven pathways. In the present issue, Xu and colleagues provide new evidence, showing that β₂-adrenoceptor over-expression leads to increased reactive oxygen species (ROS) emission, mainly caused by up-regulation of reduced nicotinamide adenine dinucleotide phosphate oxidase (Nox) 2 and 4. Increase in ROS levels is accompanied by p38 mitogen-activated protein kinase activation, fibrosis, apoptosis and cardiac dysfunction. Both Nox inhibition and administration of the antioxidant N-acetyl cysteine prevent these adverse effects. Interestingly, antioxidant treatment also prevents the increase in Nox expression, suggesting that β₂-adrenoceptor stimulation triggers a vicious cycle eventually amplified by both Nox isoforms. The possible existence of a circuitry to enhance ROS signalling and detrimental consequences on myocardial remodelling are also discussed, in light of the recent description of intracellular localization of Nox4.
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.