title: Effect of disruption of Akt-1 of lin(-)c-kit(+) stem cells on myocardial performance in infarcted heart.
abstract: OBJECTIVE
  We have demonstrated an important role of bone marrow-derived stem cells in preservation of myocardial function. We investigated whether Akt-1 of lin(-)c-kit(+) stem cells preserves ventricular function following myocardial infarction (MI).
  
  
  RESULTS
  Isolated lin(-)c-kit(+) cells were conjugated with anti-c-kit heteroconjugated to anti-vascular cell adhesion molecule to facilitate the attachment of stem cells into damaged tissues. Female severe combined immunodeficient mice were used as recipients. MI was created by ligation of the left descending artery. After 48 h, animals were divided into four groups: (i) sham (n = 5): animals underwent thoracotomy without MI; (ii) MI (n = 5): animals underwent MI and received medium; (iii) MI + wild-type (Wt) stem cells (n = 6): MI animals received 5 x 10(5) Wt lin(-)c-kit(+) stem cells; (iv) MI + Akt-1(-/-) stem cells (n = 6): MI animals received 5 x 10(5) Akt-1(-/-) lin(-)c-kit(+) stem cells. Two weeks later, left ventricular function was measured in the Langendorff mode. The peripheral administration of Wt armed stem cells into MI animals restored ventricular function, which was absent in animals receiving Akt-1(-/-) cells. Real-time PCR indicates a decrease in SRY3, a Y chromosome marker in hearts receiving Akt-1(-/-) cells. An increase in angiogenic response was demonstrated in hearts receiving Wt stem cells but not Akt-1(-/-) stem cells.
  
  
  CONCLUSIONS
  Our results demonstrate that the peripheral administration of Wt lin(-)c-kit(+) stem cells restores ventricular function and promotes angiogenic response following MI. These benefits were abrogated in MI mice receiving Akt-1(-/-) stem cells, suggesting the pivotal role of Akt-1 in mediating stem cells to protect MI hearts.
authors.affiliation: Department of Pediatrics, Women and Infants Hospital, The Warren Alpert Medical School at Brown University, Providence, RI, USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Tseng
authors.forename: Joan
authors.initials: J
authors.lastname: Stabila
authors.forename: Beth
authors.initials: B
authors.lastname: McGonnigal
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yano
authors.forename: Mao-Jing
authors.initials: MJ
authors.lastname: Yang
authors.forename: Yi-Tang
authors.initials: YT
authors.lastname: Tseng
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Davol
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Lum
authors.forename: James F
authors.initials: JF
authors.lastname: Padbury
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific; D006332:Cardiomegaly / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D002448:Cell Adhesion; D019070:Cell Lineage; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009203:Myocardial Infarction / Q000150:complications / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018919:Neovascularization, Physiologic; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000276:immunology / Q000378:metabolism*; D020127:Recovery of Function; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000201:enzymology*; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology; D016277:Ventricular Function, Left
chemical_list: D018033:Antibodies, Bispecific; D019010:Vascular Cell Adhesion Molecule-1; D019009:Proto-Oncogene Proteins c-kit; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
references.citation: Nat Med. 2005 Apr;11(4):367-8
references.pmid: 15812508
references.citation: Nature. 2004 Apr 8;428(6983):668-73
references.pmid: 15034594
references.citation: J Appl Physiol (1985). 2008 Jun;104(6):1793-800
references.pmid: 18292296
references.citation: Am J Physiol Heart Circ Physiol. 2003 Jul;285(1):H434-41
references.pmid: 12793983
references.citation: Circulation. 2001 Jul 17;104(3):330-5
references.pmid: 11457753
references.citation: Am J Physiol Heart Circ Physiol. 2005 Nov;289(5):H1834-42
references.pmid: 16006545
references.citation: Science. 1994 Dec 2;266(5190):1494-500
references.pmid: 7985018
references.citation: Inflammation. 2007 Aug;30(3-4):97-104
references.pmid: 17497204
references.citation: Nature. 2004 Apr 8;428(6983):664-8
references.pmid: 15034593
references.citation: Nature. 2001 Apr 5;410(6829):701-5
references.pmid: 11287958
references.citation: Science. 1997 Feb 14;275(5302):964-7
references.pmid: 9020076
references.citation: J Biol Chem. 2002 Oct 4;277(40):37670-7
references.pmid: 12163490
references.citation: Science. 1997 Apr 4;276(5309):71-4
references.pmid: 9082988
references.citation: Circ Res. 2004 Apr 16;94(7):884-91
references.pmid: 14988230
references.citation: J Mol Cell Cardiol. 2004 Nov;37(5):1041-52
references.pmid: 15522281
references.citation: Circulation. 2000 Feb 15;101(6):660-7
references.pmid: 10673259
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10344-9
references.pmid: 11504914
references.citation: Stem Cells. 2007 Mar;25(3):712-7
references.pmid: 17138964
references.citation: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11507-12
references.pmid: 10500207
references.citation: Circulation. 2003 Mar 11;107(9):1247-9
references.pmid: 12628942
references.citation: N Engl J Med. 2006 Sep 21;355(12):1210-21
references.pmid: 16990384
references.citation: Blood. 1994 Sep 1;84(5):1482-91
references.pmid: 7520774
references.citation: N Engl J Med. 2006 Sep 21;355(12):1222-32
references.pmid: 16990385
references.citation: Nat Med. 2003 Sep;9(9):1195-201
references.pmid: 12910262
references.citation: N Engl J Med. 2006 Sep 21;355(12):1274-7
references.pmid: 16990391
references.citation: Biotechniques. 1999 Jan;26(1):112-22, 124-5
references.pmid: 9894600
references.citation: N Engl J Med. 2002 Jan 3;346(1):5-15
references.pmid: 11777997
references.citation: Blood Cells Mol Dis. 2004 Jan-Feb;32(1):82-7
references.pmid: 14757418
references.citation: J Appl Physiol. 1976 Sep;41(3):328-31
references.pmid: 965300
references.citation: Physiol Rev. 1992 Apr;72(2):369-417
references.pmid: 1372998
references.citation: N Engl J Med. 2006 Sep 21;355(12):1199-209
references.pmid: 16990383