Constitutive glycogen synthase kinase-3α/β activity protects against chronic β-adrenergic remodelling of the heart

Abstract

Aims Glycogen synthase kinase 3 (GSK-3) signalling is implicated in the growth of the heart during development and in response to stress. However, its precise role remains unclear. We set out to characterize developmental growth and response to chronic isoproterenol (ISO) stress in knockin (KI) mice lacking the critical N-terminal serines, 21 of GSK-3α and 9 of GSK-3β respectively, required for inactivation by upstream kinases. Methods and results Between 5 and 15 weeks, KI mice grew more rapidly, but normalized heart weight and contractile performance were similar to wild-type (WT) mice. Isolated hearts of both genotypes responded comparably to acute ISO infusion with increases in heart rate and contractility. In WT mice, chronic subcutaneous ISO infusion over 14 days resulted in cardiac hypertrophy, interstitial fibrosis, and impaired contractility, accompanied by foetal gene reactivation. These effects were all significantly attenuated in KI mice. Indeed, ISO-treated KI hearts demonstrated reversible physiological remodelling traits with increased stroke volume and a preserved contractile response to acute adrenergic stimulation. Furthermore, simultaneous pharmacological inhibition of GSK-3 in KI mice treated with chronic subcutaneous ISO recapitulated the adverse remodelling phenotype seen in WT hearts. Conclusion Expression of inactivation-resistant GSK-3α/β does not affect eutrophic myocardial growth but protects against pathological hypertrophy induced by chronic adrenergic stimulation, maintaining cardiac function and attenuating interstitial fibrosis. Accordingly, strategies to prevent phosphorylation of Ser-21/9, and consequent inactivation of GSK-3α/β, may enable a sustained cardiac response to chronic β-agonist stimulation while preventing pathological remodelling.

Publication DOI: https://doi.org/10.1093/cvr/cvq061
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences > Aston Medical School
Additional Information: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2010. For permissions please email: journals.permissions@oxfordjournals.org. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.
Uncontrolled Keywords: GSK-3,remodelling,cardiac hypertrophy
Publication ISSN: 0008-6363
Last Modified: 02 Dec 2024 08:11
Date Deposited: 11 Feb 2014 09:09
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
http://cardiova ... t/87/3/494.full (Publisher URL)
PURE Output Type: Article
Published Date: 2010-08-01
Published Online Date: 2010-03-17
Authors: Webb, Ian G.
Nishino, Yasuhiro
Clark, James E.
Murdoch, Colin (ORCID Profile 0000-0002-0274-819X)
Walker, Simon J.
Makowski, Marcus R.
Botnar, Rene M.
Redwood, Simon R.
Shah, Ajay M.
Marber, Michael S.

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