Document Detail

Temporal PTEN inactivation causes proliferation of saphenous vein smooth muscle cells of human CABG conduits.
MedLine Citation:
PMID:  18363844     Owner:  NLM     Status:  MEDLINE    
Abstract Internal mammary artery (IMA) coronary artery bypass grafts (CABG) are remarkably resistant to intimal hyperplasia (IH) as compared to saphenous vein (SV) grafts following aorto-coronary anastomosis. The reason behind this puzzling difference still remains an enigma. In this study, we examined the effects of IGF-1 stimulation on the PI3K-AKT/PKB pathway mediating proliferation of smooth muscle cells (SMCs) of IMA and SV origin and the specific contribution of phosphatase and tensin homologue (PTEN) in regulating the IGF-1-PI3K-AKT/PKB axis under these conditions. Mitogenic activation with IGF-1, time-dependently stimulated the phosphorylation of PI3K and AKT/PKB in the SV SMCs to a much greater extent than the IMA. Conversely, PTEN was found to be significantly more active in IMA SMCs. Transient overexpression of PTEN in SMCs of SV and IMA inhibited AKT/PKB activity and upstream of AKT/PKB, caused a reduction of IGF-1 receptors. Downstream, PTEN overexpression in SV SMCs induced the transactivation of tumour suppressor protein p53 by down-regulating the expression of its inhibitor MDM2. However, PTEN overexpression had no significant effect on MDM2 and p53 expression in IMA SMCs. PTEN overexpression inhibited IGF-1-induced SMC proliferation in both SV and IMA. PTEN suppression, induced by siRNA transfection of IMA SMCs diminished the negative regulation of PI3K-PKB signalling leading to greater proliferative response induced by IGF-1 stimulation. Thus, we show for the first time that early inactivation of PTEN in SV SMCs leads to temporally increased activity of the pro-hyperplasia PI3K-AKT/PKB pathway leading to IH-induced vein graft occlusion. Therefore, modulation of the PI3K-AKT/PKB pathway via PTEN might be a novel and effective strategy in combating SV graft failure following CABG.
Amit K Mitra; Guanghong Jia; Deepak M Gangahar; Devendra K Agrawal
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2008-03-19
Journal Detail:
Title:  Journal of cellular and molecular medicine     Volume:  13     ISSN:  1582-4934     ISO Abbreviation:  J. Cell. Mol. Med.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2009-01-29     Completed Date:  2009-07-22     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  101083777     Medline TA:  J Cell Mol Med     Country:  Romania    
Other Details:
Languages:  eng     Pagination:  177-87     Citation Subset:  IM    
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MeSH Terms
Cell Proliferation*
Cells, Cultured
Coronary Artery Bypass*
Enzyme Activation
Gene Silencing
Graft Occlusion, Vascular
Hyperplasia / pathology
Insulin-Like Growth Factor I / metabolism
Mammary Arteries / cytology
Middle Aged
Muscle, Smooth, Vascular / cytology*
Myocytes, Smooth Muscle / cytology,  physiology*
PTEN Phosphohydrolase / genetics,  metabolism*
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins c-mdm2 / metabolism
Saphenous Vein / cytology*
Signal Transduction / physiology
Tumor Suppressor Protein p53 / metabolism
Grant Support
Reg. No./Substance:
0/Tumor Suppressor Protein p53; 67763-96-6/Insulin-Like Growth Factor I; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC Proteins c-akt; EC protein, human; EC Phosphohydrolase; EC protein, human; EC Proteins c-mdm2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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