title: Bidirectional cross-regulation between ErbB2 and β-adrenergic signalling pathways.
abstract: OBJECTIVE
  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.
  
  
  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 (ErbB2(tg)) 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 ErbB2(tg) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins Medical Institutions, MRB 807, 733 N. Broadway, Baltimore, MD 21205, USA.
authors.forename: Polina
authors.initials: P
authors.lastname: Sysa-Shah
authors.affiliation: Division of Internal Medicine, Department of Translational Medical Sciences, Federico II University, Naples, Italy.
authors.forename: Carlo G
authors.initials: CG
authors.lastname: Tocchetti
authors.affiliation: Department of Molecular Cardiology, Cleveland Clinic, Lerner Research Institute, Cleveland, OH, USA.
authors.forename: Manveen
authors.initials: M
authors.lastname: Gupta
authors.affiliation: Division of Cardiology, Department of Medicine, Medical University of Graz, Graz, Austria Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Rainer
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Byung-Hak
authors.initials: BH
authors.lastname: Kang
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins Medical Institutions, MRB 807, 733 N. Broadway, Baltimore, MD 21205, USA.
authors.forename: Frances
authors.initials: F
authors.lastname: Belmonte
authors.affiliation: Clinical Laboratory, Chinese PLA General Hospital, Beijing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins Medical Institutions, MRB 807, 733 N. Broadway, Baltimore, MD 21205, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins Medical Institutions, MRB 807, 733 N. Broadway, Baltimore, MD 21205, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins Medical Institutions, MRB 807, 733 N. Broadway, Baltimore, MD 21205, USA.
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Wei Dong
authors.initials: WD
authors.lastname: Gao
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
authors.affiliation: Cardiovascular Services, Maine Medical Center, Portland, ME, USA.
authors.forename: Rutwik
authors.initials: R
authors.lastname: Rath
authors.affiliation: Cardiovascular Services, Maine Medical Center, Portland, ME, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Sawyer
authors.affiliation: Department of Molecular Cardiology, Cleveland Clinic, Lerner Research Institute, Cleveland, OH, USA.
authors.forename: Sathyamangla V
authors.initials: SV
authors.lastname: Naga Prasad
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins Medical Institutions, MRB 807, 733 N. Broadway, Baltimore, MD 21205, USA kgabriel@jhmi.edu.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gabrielson
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology*; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D000242:Cyclic AMP; D007545:Isoproterenol; D018719:Erb-b2 Receptor Tyrosine Kinases; D018342:Receptors, Adrenergic, beta-1; C524056:Erbb2 protein, mouse
keywords: ErbB2; ErbB2 kinase inhibitors; β-Adrenergic stimulation; β-Blockers