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 1

Deletion of Gsk3a leads to cardiac hypertrophy.

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Deletion of Gsk3a leads to cardiac hypertrophy. (A) Deletion of Gsk3...
(A) Deletion of Gsk3a does not lead to compensatory upregulation of GSK-3β. Immunoblot of heart lysates from 6-month-old Gsk3a+/+ (WT) and Gsk3a–/– (KO) mice, blotted with anti–GSK-3α (top), anti–GSK-3β (middle), or loading control (anti-GAPDH, bottom). (B) Cardiomyocyte size determination. Cardiomyocytes were isolated from 6-month-old KO and WT mice, as described in Methods. Cell area was then determined in 551 KO myocytes from mice (n = 6) and 576 WT myocytes from mice (n = 6), as described in Methods. #P < 0.01 versus WT. (C) GSK-3α regulates phosphorylation of glycogen synthase, Ser641. Mice were fasted overnight, and then heart lysates were immunoblotted with anti–phospho–glycogen synthase (GS-pSer641), anti–glycogen synthase (GS), or GAPDH. The image is representative of findings from WT (n = 6) and KO (n = 6) mice. (D) Dysregulation of mTORC1 in the KO mice. Lysates of hearts from 4-month-old WT and KO mice were immunoblotted for (top to bottom) phospho–4E-BP1 Thr37/46, phospho–4E-BP1 Ser65, total 4E-BP1, phospho-p70S6K Thr389, total p70S6K, or GAPDH. Note the increase in phosphorylation of 4E-BP1 at both sites and of p70S6K in the KO.