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Bidirectional cross-regulation between ErbB2 and β-adrenergic signalling pathways
Polina Sysa-Shah1, Carlo G Tocchetti2, Manveen Gupta3
1Department of Molecular and Comparative Pathobiology, Johns Hopkins Medical Institutions, MRB 807, 733 N. Broadway, Baltimore, MD 21205, USA.
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 (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.
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.
Insights
Beta-adrenergic receptors (AR) and ErbB2 signaling form a feedback loop, where AR activation increases ErbB2 expression and activity. ErbB2 kinase activity protects the heart from beta-adrenergic stress.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- ErbB2 (a receptor tyrosine kinase) influences heart sensitivity to chemotherapy and targeted therapies.
- Mechanisms regulating ErbB2 expression and activity, particularly in the heart, remain understudied.
- Isoproterenol, a beta-adrenergic agonist, up-regulates ErbB2 in certain tissues and forms complexes with beta-adrenergic receptors (βARs) in the brain and heart.
Purpose of the Study:
- To investigate the hypothesis that beta-adrenergic receptors (AR) modulate ErbB2 signaling status.
- To elucidate the interplay between ErbB2 and βAR signaling in the myocardium.
- To determine the role of ErbB2 kinase activity in cardiac protection during beta-adrenergic stress.
Main Methods:
- Utilized HEK293 cell transfections to examine the reciprocal regulation of ErbB2 and β2AR.
- Isolated cardiomyocytes and right ventricular trabeculae from myocyte-specific ErbB2-overexpressing (ErbB2(tg)) mice.
- Performed receptor binding assays and Western blotting to assess receptor levels and signaling.
- Administered β1- and β2-AR agonists (isoproterenol) and antagonists in vivo, with and without ErbB2 kinase inhibition.
Main Results:
- ErbB2 and β2AR mutually up-regulate each other's expression in HEK293 cells.
- ErbB2 overexpression in cardiomyocytes enhanced response to a β2-agonist, while β2-antagonist reduced baseline force.
- β2AR levels were elevated in ErbB2(tg) myocardium and decreased by lapatinib (EGFR/ErbB2 inhibitor).
- Isoproterenol treatment increased myocardial ErbB2, and ErbB2 inhibition exacerbated isoproterenol-induced heart injury, reducing pAKT and pERK levels.
Conclusions:
- Myocardial ErbB2 and βAR signaling are interconnected via a feedback loop.
- βAR activation increases ErbB2 expression and activity, which in turn regulates β2AR expression.
- ErbB2 kinase activity is essential for cardioprotection against β-adrenergic stress, relevant to chemotherapy-induced cardiomyopathy.
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