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

Polina Sysa-Shah, Carlo G. Tocchetti, Manveen Gupta, Peter P. Rainer, Xiaoxu Shen, Byung Hak Kang, Frances Belmonte, Jian Li, Yi Xu, Xin Guo, Djahida Bedja, Wei Dong Gao, Nazareno Paolocci, Rutwik Rath, Douglas B. Sawyer, Sathyamangla V. Naga Prasad, Kathleen Gabrielson

Research output: Contribution to journalArticlepeer-review

Abstract

Aims 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 β2AR and ErbB2 complex in brain and heart, we hypothesized that β-adrenergic receptors (AR) modulate ErbB2 signalling status. Methods and results ErbB2 transfection of HEK293 cells up-regulates β2AR, and β2AR transfection of HEK293 up-regulates ErbB2. Interestingly, cardiomyocytes isolated from myocyte-specific ErbB2-overexpressing (ErbB2tg) mice have amplified response to selective β2-agonist zinterol, and right ventricular trabeculae baseline force generation is markedly reduced with β2-antagonist ICI-118 551. Consistently, receptor binding assays and western blotting demonstrate that β2ARs levels are markedly increased in ErbB2tg myocardium and reduced by EGFR/ErbB2 inhibitor, lapatinib. Intriguingly, acute treatment of mice with β1- and β2-AR agonist isoproterenol resulted in myocardial ErbB2 increase, while inhibition with either β1- or β2-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. Conclusion Our studies show that myocardial ErbB2 and βAR signalling are linked in a feedback loop with βAR activation leading to increased ErbB2 expression and activity, and increased ErbB2 activity regulating β2AR expression. Most importantly, ErbB2 kinase activity is crucial for cardioprotection in the setting of β-adrenergic stress, suggesting that this mechanism is important in the pathophysiology and treatment of cardiomyopathy induced by ErbB2-targeting antineoplastic drugs.

Original languageEnglish (US)
Pages (from-to)358-373
Number of pages16
JournalCardiovascular research
Volume109
Issue number3
DOIs
StatePublished - Mar 1 2016

Keywords

  • ErbB2
  • ErbB2 kinase inhibitors
  • β-Adrenergic stimulation
  • β-Blockers

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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