Low invasive angiogenic therapy for myocardial infarction by retrograde transplantation of mononuclear cells expressing the VEGF gene.
BACKGROUND
Although transplantation of mononuclear cells (MNCs) induces angiogenesis in myocardial infarction, transplantation requires a large amount of bone marrow or peripheral blood cells. We examined the effects of transplantation of peripheral MNCs expressing an exogenous vascular endothelial growth factor (VEGF) gene in a pig model of acute myocardial infarction (AMI).


METHODS
MNCs were isolated from 20 ml peripheral blood from pigs and transfected with 10 microg of human VEGF165 plasmid (phVEGF). Myocardial infarction was induced by occlusion of the mid portion of the left anterior descending coronary artery (LAD) in anesthetized pigs. At 4 h after total occlusion, 5 x 10(6) VEGF-transfected MNCs were retrogradely transplanted into the pig via the coronary vein. Cardiac function, neovascularization and histology of the ischemic tissue were evaluated 4 weeks after transplantation.


RESULTS
MNCs expressing hVEGF and infused via the coronary vein were efficiently delivered the heart in pigs with myocardial infarction. Transplantation of MNCs expressing hVEGF significantly increased left ventricular (LV) function, collateral vessels, and capillary density in heart from AMI model pigs. Transplantation of MNCs expressing hVEGF increased the wall thickness of the scar in the heart after AMI.


CONCLUSIONS
Retrograde transplantation of peripheral blood MNCs expressing hVEGF efficiently induced angiogenesis and improved the impaired LV function in hearts of pigs with AMI. These findings indicate that angiogenic cells and gene therapy may be useful to treat ischemic heart disease.
Hagikura
Kazuhiro
K
Department of Advanced Medicine, Nihon University School of Medicine, Division of Cell Regeneration and Transplantation, 30-1, Oyaguchi, Kami-machi, Itabashi-ku, 173-8610, Tokyo, Japan.
Fukuda
Noboru
N
Yokoyama
Shin-ichiro
S
Yuxin
Li
L
Kusumi
Yoshiaki
Y
Matsumoto
Taro
T
Ikeda
Yukihiro
Y
Kunimoto
Satoshi
S
Takayama
Tadateru
T
Jumabay
Medet
M
Mitsumata
Masako
M
Saito
Satoshi
S
Hirayama
Atsushi
A
Mugishima
Hideo
H
D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000637:transplantation*; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics* / Q000601:surgery / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000235:genetics*; D036102:Peripheral Blood Stem Cell Transplantation / Q000379:methods*; D034421:Sus scrofa; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics*
D042461:Vascular Endothelial Growth Factor A