GSK-3α directly regulates β-adrenergic signaling and the response of the heart to hemodynamic stress in mice
Jibin Zhou, … , Erhe Gao, Thomas Force
Jibin Zhou, … , Erhe Gao, Thomas Force
Published June 1, 2010
Citation Information: J Clin Invest. 2010;120(7):2280-2291. https://doi.org/10.1172/JCI41407.
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Research Article Cardiology

GSK-3α directly regulates β-adrenergic signaling and the response of the heart to hemodynamic stress in mice

Abstract

The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases consists of 2 highly related isoforms, α and β. Although GSK-3β has an important role in cardiac development, much remains unknown about the function of either GSK-3 isoform in the postnatal heart. Herein, we present what we believe to be the first studies defining the role of GSK-3α in the mouse heart using gene targeting. Gsk3a–/– mice over 2 months of age developed progressive cardiomyocyte and cardiac hypertrophy and contractile dysfunction. Following thoracic aortic constriction in young mice, we observed enhanced hypertrophy that rapidly transitioned to ventricular dilatation and contractile dysfunction. Surprisingly, markedly impaired β-adrenergic responsiveness was found at both the organ and cellular level. This phenotype was reproduced by acute treatment of WT cardiomyocytes with a small molecule GSK-3 inhibitor, confirming that the response was not due to a chronic adaptation to LV dysfunction. Thus, GSK-3α appears to be the central regulator of a striking range of essential processes, including acute and direct positive regulation of β-adrenergic responsiveness. In the absence of GSK-3α, the heart cannot respond effectively to hemodynamic stress and rapidly fails. Our findings identify what we believe to be a new paradigm of regulation of β-adrenergic signaling and raise concerns given the rapid expansion of drug development targeting GSK-3.

Authors

Jibin Zhou, Hind Lal, Xiongwen Chen, Xiying Shang, Jianliang Song, Yingxin Li, Risto Kerkela, Bradley W. Doble, Katrina MacAulay, Morgan DeCaul, Walter J. Koch, John Farber, James Woodgett, Erhe Gao, Thomas Force

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Figure 3

TAC in 2-month-old KO mice.

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TAC in 2-month-old KO mice. Mice underwent echocardiography and then wer...
Mice underwent echocardiography and then were subjected to TAC or sham TAC. Mice were followed with weekly echocardiography, until sacrifice at 3 weeks after TAC. (A) LV mass. Note the exaggerated hypertrophic response in the KO mice. Black triangles represent WT mice subjected to TAC; red circles represent KO mice subjected to TAC; and green and blue squares represent WT and KO shams, respectively. (B) Fractional shortening in the KO mice progressively declined over the 3 weeks after TAC, whereas fractional shortening in the WT mice remained stable. (C) EDD progressively declined in WT and KO mice for the first 2 weeks but then increased sharply in the KO mice, consistent with adverse remodeling/dilatation. (A–C) P values are for the comparison between WT versus KO mice subjected to TAC. n = 8 WT and 8 KO sham mice; n = 20 WT/TAC and 20 KO/TAC. (D) LVSP, measured by invasive hemodynamic evaluation, was decreased in the KO mice subjected to TAC. n = 8 WT and 8 KO sham mice; n = 11 WT/TAC and 9 KO/TAC. (E) Morphometrics (hypertrophy). HW/BW was determined at sacrifice in KO and WT mice undergoing TAC or sham surgery. n = 8 WT and 8 KO sham mice; n = 9 WT/TAC and 11 KO/TAC. (F) Fibrosis in the KO mice. WT and KO mice that underwent TAC were sacrificed at 3 weeks. Sections of heart tissue were stained with Masson’s trichrome. The percentage of fibrosis was determined from 10 random images taken from each of 4 KO and 4 WT mice. Original magnification, ×200.