Glycogen synthase kinase-3beta is involved in the process of myocardial hypertrophy stimulated by insulin-like growth factor-1.
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.


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.
Seimi
Satomi-Kobayashi
SK
Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan.
Seinosuke
Kawashima
K
Tsuyoshi
Sakoda
S
Tomomi
Ueyama
U
Tetsuaki
Hirase
H
Miki
Kawai
K
Ryuji
Toh
T
Kenji
Iwai
I
Mitsuhiro
Yokoyama
Y
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000139:chemically induced* / Q000201:enzymology*; D002454:Cell Differentiation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D032342:Muscle Cells / Q000201:enzymology* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007334:Insulin-Like Growth Factor I; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494920:Akt1 protein, rat; C000605508:Gsk3b protein, rat