Deletion of GSK-3b in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation (J Clin Invest, 2008, 118:3609-3618)

報告日期: 2009/05/26
報告時間: 16:05/16:55
報告學生: 蔡政潔(英文報告)
講評老師: 莫凡毅

Deletion of GSK-3β in mice leads to hypertrophic cardiomyopathy

secondary to cardiomyoblast hyperproliferation

Kerkela, R. et al., J. Clin. Invest. 2008. 118: 3609-3618.


Student: Cheng-Chieh Tsai (蔡政潔)

Commentator: Dr. Fan-E Mo (莫凡毅 教授)

Time: 16:10-17:00, May 26, 2009

Place: Room 602



Glycogen synthase kinase (GSK-3), a serine/threonine kinase, regulates a wide range of cellular processes, including embryonic development and cell fate. GSK-3 consists of two isoforms, GSK-3a and GSK-3b. Nevertheless, the precise role of the GSK-3 isoforms is still controversial. In the heart, GSK-3 is a negative regulator of cardiomyocyte hypertrophy. GSK-3 inhibition promotes proliferation and stem cell self-renewal in both neonatal and adult rat cardiomyocytes.1 Inhibiting GSK-3 results in changes of the activities of transcription factors and cell cycle regulators implicated in heart development, such as D-type cyclins and Myc family members.2 Lithium, a GSK-3 inhibitor, has been used as a drug for treatment of bipolar disorders. The past reports showed that a strong association between maternal lithium treatment during pregnancy and congenital heart defects in the offspring.3 In this paper, the authors investigated the role of GSK-3 isoforms in mammalian normal heart development by using ES cell and mice deleted for either Gsk3a or Gsk3b. They found that GSK3b, but not GSK3a, is necessary for late cardiomyocyte differentiation. Furthermore, GSK-3b deficient embryos have congenital heart defects, including double outlet RV, ventricular septal defect and significant thickened ventricular walls. They further demonstrated that the increased wall thickness was caused by cardiomyocyte hyperproliferation, but not reduced apoptosis, and was related with upregulated expression and nuclear localization of three regulators of cardiac proliferation, including cyclin D1, c-Myc and GATA4 in GSK-3b-deficient heart. Taken together, these results indicate that GSK-3b plays a key regulator for cardiomyocyte proliferation and differentiation during embryonic heart development.



1.       Tseng, A. S. et al., The GSK-3 inhibitor BIO promotes proliferation in mammalian cardiomyocytes. Chem. Biol. 13: 957-963. (2006).

2.       Sugden, P. H. et al., Glycogen synthase kinase 3 (GSK3) in the heart: a point of integration in hypertrophic signalling and a therapeutic target? A critical analysis. Br. J. Pharmacol. 153: S137-153. (2008).

3.       Cohen, L. S., et al., A reevaluation of risk of in utero exposure to lithium. JAMA. 271: 146-150. (1994).