Bidirectional cross-regulation between ErbB2 and β-adrenergic signaling pathways

Despite the observation that ErbB2 regulates sensitivity of the heart to doxorubicin or ErbB2-targeted cancer therapies, mechanisms that regulate ErbB2 expression and activity have not been studied. Since isoproterenol up-regulates ErbB2 in kidney and salivary glands and beta 2AR and ErbB2 complex in brain and heart, we hypothesized that beta-adrenergic receptors (AR) modulate ErbB2 signalling status. ErbB2 transfection of HEK293 cells up-regulates beta 2AR, and beta 2AR transfection of HEK293 up-regulates ErbB2. Interestingly, cardiomyocytes isolated from myocyte-specific ErbB2-overexpressing (ErbB2 (tg)) mice have amplified response to selective beta 2-agonist zinterol, and right ventricular trabeculae baseline force generation is markedly reduced with beta 2-antagonist ICI-118 551. Consistently, receptor binding assays and western blotting demonstrate that beta 2ARs levels are markedly increased in ErbB2(tg) myocardium and reduced by EGFR/ErbB2 inhibitor, lapatinib. Intriguingly, acute treatment of mice with beta 1- and beta 2-AR agonist isoproterenol resulted in myocardial ErbB2 increase, while inhibition with either beta 1- or beta 2-AR antagonist did not completely prevent isoproterenol-induced ErbB2 expression. Furthermore, inhibition of ErbB2 kinase predisposed mice hearts to injury from chronic isoproterenol treatment while significantly reducing isoproterenol-induced pAKT and pERK levels, suggesting ErbB2's role in transactivation in the heart. Our studies show that myocardial ErbB2 and beta AR signalling are linked in a feedback loop with beta AR activation leading to increased ErbB2 expression and activity, and increased ErbB2 activity regulating beta 2AR expression. Most importantly, ErbB2 kinase activity is crucial for cardioprotection in the setting of beta-adrenergic stress, suggesting that this mechanism is important in the pathophysiology and treatment of cardiomyopathy induced by ErbB2-targeting antineoplastic drugs.