Effect of disruption of Akt-1 of lin(-)c-kit(+) stem cells on myocardial performance in infarcted heart.
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.
Tseng
Andy
A
Department of Pediatrics, Women and Infants Hospital, The Warren Alpert Medical School at Brown University, Providence, RI, USA.
Stabila
Joan
J
McGonnigal
Beth
B
Yano
Naohiro
N
Yang
Mao-Jing
MJ
Tseng
Yi-Tang
YT
Davol
Pamela A
PA
Lum
Lawrence G
LG
Padbury
James F
JF
Zhao
Ting C
TC
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
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
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