Cardioprotective Effect of Beta-3 Adrenergic Receptor Agonism

Objective The aim of this study is to determine if activation of β3-adrenoceptor (β3-AR) and downstream signaling of NOS isoforms protects the heart from failure and hypertrophy induced by pressure overload. Background β3-AR and its downstream signaling pathways are recognized as novel modulators of heart function. Unlike _1- and _2-ARs, _3-ARs are stimulated at high catecholamine concentrations and induce negative inotropic effects, serving as a “brake” to protect the heart from catecholamine overstimulation. Methods C57BL/6J and nNOS knock-out mice were assigned to receive transverse aortic constriction (TAC), BRL37344 (β3-agonist, BRL0.1 mg/kg/hour), or both. Results Three weeks of BRL treatment in wild type mice attenuated left ventricular dilation and systolic dysfunction, and partially reduced cardiac hypertrophy induced by TAC. This effect was associated with increased nitric oxide (NO) production and superoxide suppression. TAC decreased endothelial NO synthase (eNOS) dimerization, indicating eNOS uncoupling, which was not reversed by BRL treatment. However, nNOS protein expression was up-regulated 2-fold by BRL, and the suppressive effect of BRL on superoxide generation was abrogated by acute neuronal NO synthase (nNOS) inhibition. Furthermore, BRL cardioprotective effects were actually detrimental in nNOS−/− mice. Conclusion These results are the first to show in vivo cardioprotective effects of β3-AR specific agonism in pressure overload hypertrophy and heart failure, and support nNOS as the primary downstream NOS isoform in maintaining NO and reactive oxygen species (ROS) balance in the failing heart.