Hepatocyte growth factor protects endothelial progenitor cell from damage of low-density lipoprotein cholesterol via the PI3K/Akt signaling pathway.
Risk factors for coronary heart disease including low-density lipoprotein (LDL) cholesterol can reduce the number and activity of endothelial progenitor cells (EPCs), thereby hindering their usefulness for treating cardiovascular disease in transplants. The aim of this study was to investigate whether hepatocyte growth factor (HGF) can protect EPCs from the inhibition caused by LDL cholesterol. EPCs derived from mouse bone marrow were isolated and cultured in medium supplemented with different concentrations of LDL cholesterol. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, modified Boyden chambers and flow cytometry were used to evaluate EPC proliferation, migration and apoptosis. The role of Akt in this process was also evaluated through observing the expressions of total Akt and Akt phosphorylation, and pharmacological analysis. Our results indicate that LDL cholesterol inhibits the proliferation and migration of EPCs, and induces their apoptosis. However, HGF improves the activity of EPCs inhibited by LDL cholesterol, and it simultaneously decreases EPC apoptosis induced by LDL cholesterol. Blockade of phosphoinositide-3 kinase (PI3K) by Ly294002 attenuates the effect of HGF. Furthermore, our experiments suggest that HGF increases the level of phosphorylated Akt in EPCs rather than Akt. However, PI3K inhibitor reduces the increase of phosphorylated Akt level induced by HGF. These findings suggest HGF promotes endothelial progenitor cells migration, proliferation and survival impaired by low-density lipoprotein cholesterol via the PI3K/Akt signaling pathway.
Yu
XueJun
X
Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, 400037 Chongqing, People's Republic of China.
Song
MingBao
M
Chen
JianFei
J
Zhu
GuangXu
G
Zhao
Gang
G
Wang
Hong
H
Hunag
Lan
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D008078:Cholesterol, LDL / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects*; D042783:Endothelial Cells / Q000166:cytology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology
D008078:Cholesterol, LDL; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt
Nat Rev Cancer. 2002 Apr;2(4):289-300
12001990
Biochem Biophys Res Commun. 2004 Nov 5;324(1):276-80
15465014
Ann Thorac Surg. 2002 Jun;73(6):1919-25; discussion 1926
12078791
Nat Med. 2001 Apr;7(4):430-6
11283669
Catheter Cardiovasc Interv. 2007 Oct 1;70(4):477-84
17894361
Nat Med. 2001 Nov;7(11):1194-201
11689883
Circ Res. 2003 Jul 25;93(2):e17-24
12829619
Circ Res. 2004 Aug 20;95(4):343-53
15321944
Cardiovasc Pathol. 2004 Nov-Dec;13(6):306-12
15556776
Endocrinology. 2007 May;148(5):2085-94
17289842
Am J Pathol. 2005 Jul;167(1):275-84
15972971
Surgery. 2004 Jun;135(6):657-61
15179372
J Lipid Res. 2006 Jun;47(6):1227-37
16522925
Am J Physiol Lung Cell Mol Physiol. 2008 Apr;294(4):L778-86
18245266
N Engl J Med. 2003 Feb 13;348(7):593-600
12584367
Stem Cells. 2007 Dec;25(12):3234-43
17901400
Arthritis Rheum. 2006 Aug;54(8):2605-15
16868984
Science. 1997 Feb 14;275(5302):964-7
9020076
Circ Res. 2001 Jul 6;89(1):E1-7
11440984
Vox Sang. 2005 Jan;88(1):1-9
15663716
Circulation. 2005 Jul 5;112(1):3-5
15998692
N Engl J Med. 2005 Sep 8;353(10):999-1007
16148285
FEBS Lett. 2004 Jan 2;556(1-3):249-52
14706858
Circ Res. 2001 Feb 2;88(2):167-74
11157668
Biochem Biophys Res Commun. 2006 Jun 2;344(2):658-66
16630544
Circulation. 2003 Dec 23;108(25):3115-21
14676142
Nihon Shokakibyo Gakkai Zasshi. 2002 Apr;99(4):365-78
11979734
Arterioscler Thromb Vasc Biol. 2006 Feb;26(2):257-66
16322535
PLoS One. 2007 Oct 10;2(10):e975
17925881
J Am Coll Cardiol. 2006 May 2;47(9):1786-95
16682302
Nat Rev Mol Cell Biol. 2003 Dec;4(12):915-25
14685170
J Eval Clin Pract. 2009 Feb;15(1):212-6
19239605
J Pharmacol Sci. 2007 Apr;103(4):398-407
17409628
Blood. 1998 May 15;91(10):3527-61
9572988
Curr Pharm Des. 2007;13(16):1699-713
17584100
Circulation. 2004 Apr 13;109(14):1769-75
15066951