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Temporal PTEN inactivation causes proliferation of saphenous vein smooth muscle cells of human CABG conduits
- Source :
- Journal of Cellular and Molecular Medicine
- Publication Year :
- 2008
- Publisher :
- Wiley, 2008.
-
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.
- Subjects :
- PTEN
Intimal hyperplasia
vein-graft disease
030204 cardiovascular system & hematology
Muscle, Smooth, Vascular
Phosphatidylinositol 3-Kinases
0302 clinical medicine
Tensin
Coronary Artery Bypass
Insulin-Like Growth Factor I
CABG
Cells, Cultured
0303 health sciences
Graft Occlusion, Vascular
Proto-Oncogene Proteins c-mdm2
Articles
Middle Aged
internal mammary artery
IGF-1
cardiovascular system
Molecular Medicine
Phosphorylation
Signal transduction
Vein graft disease
intimal hyperplasia
Signal Transduction
Myocytes, Smooth Muscle
Biology
restenosis
saphenous vein
03 medical and health sciences
medicine
Humans
Gene Silencing
Mammary Arteries
Protein kinase B
PI3K/AKT/mTOR pathway
Aged
Cell Proliferation
030304 developmental biology
Hyperplasia
PTEN Phosphohydrolase
Cell Biology
medicine.disease
Enzyme Activation
biology.protein
Cancer research
Tumor Suppressor Protein p53
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 15821838
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- Journal of Cellular and Molecular Medicine
- Accession number :
- edsair.doi.dedup.....b1464a76e3d52fa719f68611a7427c9d