Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation Research
Search: search_blue_button Advanced Search
Circulation Research. 2007;101:1164-1174
Published online before print September 27, 2007, doi: 10.1161/CIRCRESAHA.107.160614
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow All Versions of this Article:
101/11/1164    most recent
CIRCRESAHA.107.160614v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hirotani, S.
Right arrow Articles by Sadoshima, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hirotani, S.
Right arrow Articles by Sadoshima, J.
Related Collections
Right arrow Cardio-renal physiology/pathophysiology
Right arrow Hypertrophy
Right arrow Animal models of human disease
Right arrow Cell signalling/signal transduction
Right arrowRelated Article
(Circulation Research. 2007;101:1164.)
© 2007 American Heart Association, Inc.


Integrative Physiology

Inhibition of Glycogen Synthase Kinase 3ß During Heart Failure Is Protective

Shinichi Hirotani*, Peiyong Zhai*, Hideharu Tomita, Jonathan Galeotti, Juan Pablo Marquez, Shumin Gao, Chull Hong, Atsuko Yatani, Jesús Avila, Junichi Sadoshima

From the Cardiovascular Research Institute (S.H., P.Z., H.T., J.G., J.P.M., S.G., C.H., A.Y., J.S.), Department of Cell Biology and Molecular Medicine, University of Medicine & Dentistry of New Jersey, New Jersey Medical School, Newark; and Centro de Biología Molecular "Severo Ochoa" (J.A.), Facultad de Ciencias, Campus de Cantoblanco, Universidad Autónoma de Madrid, Spain.

Correspondence to Junichi Sadoshima, MD, PhD, Cardiovascular Research Institute, UMDNJ, 185 South Orange Ave, MSB G-609, Newark, NJ 07103. E-mail Sadoshju{at}umdnj.edu

Glycogen synthase kinase (GSK)-3, a negative regulator of cardiac hypertrophy, is inactivated in failing hearts. To examine the histopathological and functional consequence of the persistent inhibition of GSK-3ß in the heart in vivo, we generated transgenic mice with cardiac-specific overexpression of dominant negative GSK-3ß (Tg-GSK-3ß-DN) and tetracycline-regulatable wild-type GSK-3ß. GSK-3ß-DN significantly reduced the kinase activity of endogenous GSK-3ß, inhibited phosphorylation of eukaryotic translation initiation factor 2B{epsilon}, and induced accumulation of ß-catenin and myeloid cell leukemia-1, confirming that GSK-3ß-DN acts as a dominant negative in vivo. Tg-GSK-3ß-DN exhibited concentric hypertrophy at baseline, accompanied by upregulation of the {alpha}-myosin heavy chain gene and increases in cardiac function, as evidenced by a significantly greater Emax after dobutamine infusion and percentage of contraction in isolated cardiac myocytes, indicating that inhibition of GSK-3ß induces well-compensated hypertrophy. Although transverse aortic constriction induced a similar increase in hypertrophy in both Tg-GSK-3ß-DN and nontransgenic mice, Tg-GSK-3ß-DN exhibited better left ventricular function and less fibrosis and apoptosis than nontransgenic mice. Induction of the GSK-3ß transgene in tetracycline-regulatable wild-type GSK-3ß mice induced left ventricular dysfunction and premature death, accompanied by increases in apoptosis and fibrosis. Overexpression of GSK-3ß-DN in cardiac myocytes inhibited tumor necrosis factor-{alpha}–induced apoptosis, and the antiapoptotic effect of GSK-3ß-DN was abrogated in the absence of myeloid cell leukemia-1. These results suggest that persistent inhibition of GSK-3ß induces compensatory hypertrophy, inhibits apoptosis and fibrosis, and increases cardiac contractility and that the antiapoptotic effect of GSK-3ß inhibition is mediated by myeloid cell leukemia-1. Thus, downregulation of GSK-3ß during heart failure could be compensatory.


Key Words: GSK-3ß • heart failure • cardiac hypertrophy • apoptosis


Related Article:

Not All Hypertrophy Is Created Equal
Ronglih Liao and Thomas Force
Circ. Res. 2007 101: 1069-1072. [Full Text] [PDF]



This article has been cited by other articles:


Home page
Circ. Res.Home page
R. Liao and T. Force
Not All Hypertrophy Is Created Equal
Circ. Res., November 26, 2007; 101(11): 1069 - 1072.
[Full Text] [PDF]