title: Rapamycin inhibits re-endothelialization after percutaneous coronary intervention by impeding the proliferation and migration of endothelial cells and inducing apoptosis of endothelial progenitor cells.
abstract: Endothelial-cell function is important in the healing of damaged endothelium after percutaneous coronary artery damage. In 3 different animal models, we sought to determine whether rapamycin (sirolimus) affects the proliferation and migration of endothelial cells and endothelial progenitor cells. First, after we implanted stents in dogs, we found that re-endothelialization was impeded more by drug-eluting stents than by bare-metal stents, 30 days after percutaneous coronary intervention. Second, in vitro in rats, we found that 1-100 ng/mL of rapamycin time- and dose-dependently inhibited proliferation over 72 hr (with effects evident as early as 24 hr) and also dose-dependently induced endothelial progenitor-cell apoptosis. Finally, in vivo in rats, we observed that vascular endothelial growth factor expression was decreased after 5 days of rapamycin treatment. We conclude that rapamycin impedes re-endothelialization after drug-eluting stent implantation by inhibiting the proliferation and migration of coronary endothelial cells, inducing endothelial progenitor-cell apoptosis, and decreasing vascular endothelial growth factor expression in the circulation.
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China.
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Liu
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.forename: Wen-Yong
authors.initials: WY
authors.lastname: Wang
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Li
authors.forename: Yi-Meng
authors.initials: YM
authors.lastname: Liu
authors.forename: Rui-An
authors.initials: RA
authors.lastname: Wang
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Guo
authors.forename: Hai-Chang
authors.initials: HC
authors.lastname: Wang
mesh_terms: D015906:Angioplasty, Balloon, Coronary / Q000295:instrumentation*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D054855:Drug-Eluting Stents; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008670:Metals; D023421:Models, Animal; D011474:Prosthesis Design; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000008:administration & dosage*; D013234:Stem Cells / Q000187:drug effects* / Q000473:pathology; D015607:Stents; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D002317:Cardiovascular Agents; D008670:Metals; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D020123:Sirolimus
references.citation: Circulation. 2002 Oct 29;106(18):2379-84
references.pmid: 12403670
references.citation: N Engl J Med. 2003 Oct 2;349(14):1315-23
references.pmid: 14523139
references.citation: Med Res Rev. 1994 Jan;14(1):1-22
references.pmid: 8309312
references.citation: J Am Soc Nephrol. 1999 Jun;10(6):1366-80
references.pmid: 10361877
references.citation: J Am Coll Cardiol. 2006 Jul 4;48(1):193-202
references.pmid: 16814667
references.citation: J Am Coll Cardiol. 2006 Oct 17;48(8):1538-47
references.pmid: 17045885
references.citation: Circulation. 2002 Sep 3;106(10):1195-8
references.pmid: 12208792
references.citation: Circ Res. 1995 Mar;76(3):412-7
references.pmid: 7532117
references.citation: Circulation. 2001 Sep 4;104(10):1188-93
references.pmid: 11535578
references.citation: Circulation. 1998 Feb 17;97(6):581-8
references.pmid: 9494029
references.citation: Mol Cell Biol. 2005 Oct;25(19):8496-506
references.pmid: 16166632
references.citation: Lancet. 2004 Oct 23-29;364(9444):1466-7
references.pmid: 15500872
references.citation: Cell Prolif. 2006 Apr;39(2):117-25
references.pmid: 16542347
references.citation: Circulation. 2003 Jul 8;108(1):2-5
references.pmid: 12847051
references.citation: Circulation. 2002 Apr 23;105(16):1970-5
references.pmid: 11997285
references.citation: J Clin Invest. 1996 Nov 15;98(10):2277-83
references.pmid: 8941644
references.citation: Cancer Res. 2000 Mar 15;60(6):1541-5
references.pmid: 10749120
references.citation: Am J Cardiol. 2005 Jun 15;95(12):1469-72
references.pmid: 15950574
references.citation: Circulation. 2005 Sep 27;112(13):2002-11
references.pmid: 16172265
references.citation: JAMA. 2005 May 4;293(17):2126-30
references.pmid: 15870416
references.citation: J Cell Sci. 1998 Dec 18;111 ( Pt 24):3621-31
references.pmid: 9819353
references.citation: Exp Cell Res. 2004 Oct 15;300(1):65-71
references.pmid: 15383315
references.citation: Am J Cardiol. 2007 Mar 15;99(6):774-8
references.pmid: 17350363
references.citation: Lancet. 1989 Jul 22;2(8656):227
references.pmid: 2568561
references.citation: J Cardiovasc Pharmacol. 2006 Dec;48(6):286-92
references.pmid: 17204907
references.citation: Circulation. 2007 Feb 6;115(5):553-61
references.pmid: 17261663
references.citation: Nat Med. 2003 Jun;9(6):702-12
references.pmid: 12778169
references.citation: Circulation. 1999 Apr 27;99(16):2164-70
references.pmid: 10217658
references.citation: J Am Coll Cardiol. 2006 Jan 3;47(1):205-7
references.pmid: 16386687
references.citation: Nat Med. 2002 Feb;8(2):128-35
references.pmid: 11821896
references.citation: N Engl J Med. 2002 Jun 6;346(23):1773-80
references.pmid: 12050336
references.citation: Lancet. 2004 Oct 23-29;364(9444):1519-21
references.pmid: 15500897
references.citation: Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12574-8
references.pmid: 7809080
references.citation: Am J Cardiol. 1998 Apr 9;81(7A):14E-17E
references.pmid: 9551589
references.citation: Cardiovasc Res. 2004 Sep 1;63(4):617-24
references.pmid: 15306217
references.citation: Circulation. 2007 Feb 27;115(8):1051-8
references.pmid: 17325255
references.citation: N Engl J Med. 1994 Aug 25;331(8):489-95
references.pmid: 8041413
references.citation: Circ Res. 2006 Jun 9;98(11):1405-13
references.pmid: 16645141
references.citation: Invest Ophthalmol Vis Sci. 2005 Feb;46(2):454-60
references.pmid: 15671269
references.citation: Clin Biochem. 1997 Mar;30(2):135-42
references.pmid: 9127695
references.citation: Rev Cardiovasc Med. 2004 Winter;5(1):9-15
references.pmid: 15029110
references.citation: N Engl J Med. 1999 Dec 23;341(26):1949-56
references.pmid: 10607811
references.citation: Life Sci. 1996;58(5):373-95
references.pmid: 8594303
references.citation: Coron Artery Dis. 2002 May;13(3):183-8
references.pmid: 12131023
references.citation: N Engl J Med. 1994 Aug 25;331(8):496-501
references.pmid: 8041414
references.citation: Transplant Proc. 1991 Feb;23(1 Pt 1):521-4
references.pmid: 1703698
references.citation: Circulation. 2003 Nov 25;108(21):2710-5
references.pmid: 14597586
references.citation: Cell Res. 2008 Jul;18(7):792-9
references.pmid: 18560380
references.citation: Circulation. 2006 Nov 14;114(20):2154-62
references.pmid: 17060386
references.citation: N Engl J Med. 2000 Aug 10;343(6):385-91
references.pmid: 10933737
references.citation: Eur J Pharmacol. 2005 Nov 7;524(1-3):19-29
references.pmid: 16271360
references.citation: Circulation. 2007 Mar 20;115(11):1440-55; discussion 1455
references.pmid: 17344324
references.citation: J Am Coll Cardiol. 2005 Mar 15;45(6):941-6
references.pmid: 15766833
references.citation: N Engl J Med. 1999 Jul 29;341(5):319-27
references.pmid: 10423466
references.citation: EMBO J. 1999 Jul 15;18(14):3964-72
references.pmid: 10406801
references.citation: J Biol Chem. 1995 Jan 13;270(2):815-22
references.pmid: 7822316
references.citation: Nature. 1994 Jun 30;369(6483):756-8
references.pmid: 8008069
references.citation: Lancet. 2004 Aug 14-20;364(9434):583-91
references.pmid: 15313358