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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.
Cardiovascular Research
|December 23, 2015
Summary
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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