1. Glycogen synthase kinase-3beta is involved in the process of myocardial hypertrophy stimulated by insulin-like growth factor-1.
- Author
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Seimi SK, Seinosuke K, Tsuyoshi S, Tomomi U, Tetsuaki H, Miki K, Ryuji T, Kenji I, and Mitsuhiro Y
- Subjects
- Androstadienes pharmacology, Animals, Animals, Newborn, Cell Differentiation drug effects, Chromones pharmacology, Enzyme Inhibitors pharmacology, Glycogen Synthase Kinase 3 antagonists & inhibitors, Glycogen Synthase Kinase 3 beta, Morpholines pharmacology, Muscle Cells pathology, Myocardium pathology, Phosphatidylinositol 3-Kinases metabolism, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-akt, Rats, Rats, Sprague-Dawley, Signal Transduction drug effects, Wortmannin, Cardiomegaly chemically induced, Cardiomegaly enzymology, Glycogen Synthase Kinase 3 metabolism, Insulin-Like Growth Factor I pharmacology, Muscle Cells enzymology
- Abstract
Background: Glycogen synthase kinase-3 beta (GSK-3beta) is involved in many cellular processes, such as metabolism, apoptosis, differentiation and proliferation. Insulin-like growth factor-1 (IGF-1), which is well known to have a hypertrophic effect on cardiomyocytes, inactivates (phosphorylates) GSK-3beta in some cell types. The role of GSK-3beta in cardiomyocytes as a negative regulator of cardiac hypertrophy has been recently reported and the present study investigated the role of GSK-3beta in the cardiac hypertrophy of cultivated neonatal rat cardiomyocytes induced by IGF-1., Methods and Results: First, the IGF-1 induced signal transduction leading to GSK-3beta in neonatal rat cardiomyocytes was examined. The phosphatidylinositol (PI) 3-kinase/Akt/GSK-3 beta signaling induced by IGF-1 was investigated using inhibitors of PI 3-kinase and Ad AktAA, a dominant negative form of Akt. Furthermore, using Ad MEK DN, a dominant negative form of MEK, it was found that MEK negatively regulates Akt phosphorylation upon IGF-1 stimulation. Next, it was examined whether GSK-3beta acts as a negative regulator in the cardiac hypertrophy induced by IGF-1. Sustained stimulation by IGF-1 caused cardiac hypertrophy in protein synthesis and cellular morphology, and overexpression of unphosphorylatable GSK-3beta (Ad GSK-3beta S9A) repressed these hypertrophic effects of IGF-1., Conclusions: GSK-3beta may play an important role as a negative regulator of cardiac hypertrophy induced by IGF-1.
- Published
- 2004
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