Glycogen synthase kinase-3 (GSK-3) is a proposed drug target for a wide variety of diseases, from stroke and diabetes to Alzheimer’s disease and bipolar disorder. The element lithium is the only currently approved drug that inhibits GSK-3. However, since maternal lithium treatment has been implicated in congenital heart defects, this raises concern that new GSK-3-inhibitors might likewise cause similar abnormalities. In order to determine the role of GSK-3 in heart development, Kerkela et al. studied knockout mice lacking either GSK-3αor GSK-3βisoforms. Whereas GSK-3α-null mice had no heart defects, GSK-3β-null mice died before birth. Further analysis of GSK-3β-deficient embryos and embryonic stem cells demonstrated that hyper-proliferation of cardiomyocytes during development caused congenital cardiomyopathy. This study shows that GSK-3βis a regulator of cardiac development, and highlights potential problems in using GSK-3 antagonists in women of childbearing age.
Kerkela
R.
, Kockeritz
L.
, Macaulay
K.
, Zhou
J.
, Doble
B. W.
, Beahm
C.
, Greytak
S.
, Woulfe
K.
, Trivedi
C. M.
, Woodgett
J. R.
, et al. . (2008
). Deletion of GSK-3beta in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation
. J. Clin. Invest.
Oct 1 [Epub ahead of print]
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