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

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 lack...

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Bibliographic Details
Published in:Cardiovascular research 2010-08, Vol.87 (3), p.494-503
Main Authors: Webb, Ian G, Nishino, Yasuhiro, Clark, James E, Murdoch, Colin, Walker, Simon J, Makowski, Marcus R, Botnar, Rene M, Redwood, Simon R, Shah, Ajay M, Marber, Michael S
Format: Article
Language:English
Subjects:
Adrenergic beta-Agonists
Age Factors
Animals
Apoptosis
Cardiomegaly - chemically induced
Cardiomegaly - enzymology
Cardiomegaly - genetics
Cardiomegaly - pathology
Cardiomegaly - physiopathology
Cardiomegaly - prevention & control
Disease Models, Animal
Enzyme Activation
Fibrosis
Gene Expression Regulation
Genotype
Glycogen Synthase Kinase 3 - antagonists & inhibitors
Glycogen Synthase Kinase 3 - genetics
Glycogen Synthase Kinase 3 - metabolism
Glycogen Synthase Kinase 3 beta
Heart Rate
Isoproterenol
Mice
Mice, Transgenic
Myocardial Contraction
Myocardium - enzymology
Myocardium - pathology
Phenotype
Phosphorylation
Protein Kinase Inhibitors - pharmacology
Stroke Volume
Ventricular Function
Ventricular Remodeling
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Summary: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-3alpha and 9 of GSK-3beta respectively, required for inactivation by upstream kinases. 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. Expression of inactivation-resistant GSK-3alpha/beta 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-3alpha/beta, may enable a sustained cardiac response to chronic beta-agonist stimulation while preventing pathological remodelling.
ISSN:1755-3245
DOI:10.1093/cvr/cvq061