NDLI: Akt regulates the survival of vascular smooth muscle cells via inhibition of FoxO3a and GSK3.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Allard, David Bennett, Martin R. Figg, Nichola Littlewood, Trevor D.
Description	Author Affiliation: Allard D ( Division of Cardiovascular Medicine, University of Cambridge, Box 110, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom.)
Abstract	Apoptosis of vascular smooth muscle cells (VSMCs) may lead to atherosclerotic plaque instability and rupture, resulting in myocardial infarction, stroke, and sudden death. However, the molecular mechanisms mediating survival of VSMCs in atherosclerotic plaques remain unknown. Although plaque VSMCs exhibit increased susceptibility to apoptosis and reduced expression of the IGF1 receptor (IGF1R) when compared with normal VSMCs, a causative effect has not been established. Here we show that increased expression of the IGF1R can rescue plaque VSMCs from oxidative stress-induced apoptosis, demonstrating that IGF-1 signaling is a critical regulator of VSMC survival. Akt mediates the majority of the IGF1R survival signaling, and ectopic activation of Akt was sufficient to protect VSMCs in vitro. Both IGF1R and phospho-Akt expression were reduced in human plaque (intimal) VSMCs when compared with medial VSMCs, suggesting that Akt mediates survival signaling in atherosclerosis. Importantly, downstream targets of Akt were identified that mediate its protective effect as inhibition of FoxO3a or GSK3 by Akt-dependent phosphorylation protected VSMCs in vitro. We conclude that Akt and its downstream targets FoxO3a and GSK3 regulate a survival pathway in VSMCs and that their deregulation due to a reduction of IGF1R signaling may promote apoptosis in atherosclerosis.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	28
Volume Number	283
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2008-07-11
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Apoptosis Forkhead Transcription Factors Metabolism Glycogen Synthase Kinase 3 Muscle, Smooth, Vascular Myocytes, Smooth Muscle Proto-Oncogene Proteins C-akt Receptor, IGF Type 1 Animals Atherosclerosis Pathology Cell Survival Oxidative Stress Rats, Wistar Signal Transduction Research Support, Non-U.S. Gov't Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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