Insulin-like growth factor-1 induces phosphorylation of PI3K-Akt/PKB to potentiate proliferation of smooth muscle cells in human saphenous vein.
Coronary revascularization by coronary artery bypass grafting (CABG) is recommended in patients with recurrent myocardial ischemia. However, the long-term results of CABG using saphenous vein (SV) graft, compared to internal mammary artery (IMA) graft, have not been satisfactory. The SV graft failure is due to the development of intimal hyperplasia, a process characterized by abnormal migration and proliferation of smooth muscle cells (SMCs) in the intimal layer of the vein graft. Insulin growth factor 1 (IGF-1) is a major mitogenic growth factor released at the site of the shear stress-induced graft injury. This study, for the first time, compares the extent of IGF-1-PI3K-Akt activation in isolated human bypass graft conduits. Human SV and IMA vessels were collected and SMCs isolated and cultured. In cultured SMCs, effect of IGF-1 was examined on total and phosphorylated PI3K, Akt and IGF-1R by Western blot analysis. Cell proliferation was measured using BrdU ELISA. There was no significant difference in the basal expression of phosphorylated PI3K, Akt and IGF-1R in SV and IMA SMCs from human bypass conduits. However, we observed an upregulation of IGF-1 receptors in the SV SMCs in response to IGF-1 stimulation with no effect in IMA SMCs. Furthermore, the immunoblotting and cellular activation of signaling ELISA (CASE) assay demonstrated a significantly higher activity of both PI3K and Akt in IGF-1-stimulated SV SMCs than IMA. This was inhibited by an IGF-1R blocking antibody. IGF-1 induced proliferation in both SV and IMA SMCs was inhibited by a PI3K inhibitor, wortmannin. These data demonstrate differential activity of IGF-1-induced PI3K-Akt activation, which was quantitatively and temporally greater in SV SMCs than in the IMA. This, at least in part, could explain the greater propensity of the SV conduits than the IMA to undergo intimal hyperplasia following CABG.
Jia
Guanghong
G
Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA. dkagr@creighton.edu
Mitra
Amit K
AK
Gangahar
Deepak M
DM
Agrawal
Devendra K
DK
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000368:Aged; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D008323:Mammary Arteries / Q000166:cytology / Q000378:metabolism; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D012501:Saphenous Vein / Q000166:cytology / Q000378:metabolism
D064413:3-Phosphoinositide-Dependent Protein Kinases; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1
Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H1051-7
17040964
Nature. 2001 Dec 13;414(6865):799-806
11742412
Circ Res. 2008 Mar 28;102(6):653-60
18239136
Circ Res. 2000 Feb 4;86(2):125-30
10666406
J Vasc Surg. 2007 May;45(5):1022-8
17466797
J Mol Cell Cardiol. 2001 Oct;33(10):1777-89
11603921
Am J Physiol Heart Circ Physiol. 2009 Dec;297(6):H2015-25
19783773
J Clin Endocrinol Metab. 2010 Mar;95(3):1220-8
20080849
Circ Res. 2005 Mar 4;96(4):398-400
15692088
J Cell Mol Med. 2009 Jan;13(1):177-87
18363844
J Surg Res. 2007 Sep;142(1):137-42
17624368
Arterioscler Thromb Vasc Biol. 2006 May;26(5):1058-65
16456091
Autophagy. 2007 Jan-Feb;3(1):63-4
17172800
J Biol Chem. 2010 Mar 26;285(13):9535-9544
20042608
Arterioscler Thromb Vasc Biol. 2007 Aug;27(8):1744-51
17541019
Biochem Biophys Res Commun. 2010 Apr 9;394(3):786-91
20230795
Circ Res. 2003 Nov 14;93(10):925-31
14563713
Cancer Cell. 2004 Mar;5(3):221-30
15050914
J Mol Endocrinol. 2009 Dec;43(6):231-9
19589910
Arterioscler Thromb Vasc Biol. 2010 Mar;30(3):471-6
19965784
J Vasc Res. 2003 Mar-Apr;40(2):97-104
12808345
J Biol Chem. 2006 Jun 2;281(22):15099-109
16554298
Circ Res. 2005 Apr 1;96(6):635-42
15731459
Arterioscler Thromb Vasc Biol. 2006 Mar;26(3):611-7
16385087
J Mol Cell Cardiol. 2008 May;44(5):882-90
18405916
Circ Res. 2005 Feb 4;96(2):197-206
15591231
Biochim Biophys Acta. 2003 Oct 20;1630(1):35-40
14580677
Breast Dis. 2003;17:41-7
15687676