Cell transplantation for the treatment of acute myocardial infarction using vascular endothelial growth factor-expressing skeletal myoblasts.
BACKGROUND
Vascular endothelial growth factor (VEGF) is a promising reagent for inducing myocardial angiogenesis. Skeletal myoblast transplantation has been shown to improve cardiac function in chronic heart failure models by regenerating muscle. We hypothesized that transplantation of VEGF-expressing myoblasts could effectively treat acute myocardial infarction by providing VEGF-induced cardioprotection through vasodilatation in the early phase, followed by angiogenesis effects in salvaging ischemic host myocardium combined with the functional benefits of newly formed, skeletal myoblast-derived muscle in the later phase.


RESULTS
Primary rat skeletal myoblasts were transfected with the human VEGF(165) gene using hemagglutinating virus of Japan-liposome with >95% transfection efficiency. Four million of these myoblasts (VEGF group), control-transfected myoblasts (control group), or medium only (medium group) was injected into syngeneic rat hearts 1 hour after left coronary artery occlusion. Myocardial VEGF-expression increased for 2 weeks in the VEGF group, resulting in enhanced angiogenesis without the formation of tumors. Grafted myoblasts had differentiated into multinucleated myotubes within host myocardium. Infarct size (33.3+/-1.4%, 38.1+/-1.4%, and 43.7+/-1.6% for VEGF, control, and medium groups, respectively; P=0.0005) was significantly reduced with VEGF treatment, and cardiac function improved in the VEGF group (maximum dP/dt: 4072.0+/-93.6, 3772.5+/-101.1, and 3482.5+/-90.6 mm Hg/s in the 3 groups, respectively; P=0.0011; minimum dP/dt: -504.2+/-68.5, -2311.3+/-57.0, and -2124.0+/-57.9 mm Hg/s, respectively; P=0.0008).


CONCLUSIONS
This combined strategy of cell transplantation with gene therapy could be of importance for the treatment of acute myocardial infarction.
Suzuki
K
K
Department of Cardiothoracic Surgery, Imperial College School of Medicine, Heart Science Centre, Harefield Hospital, Middlesex, UK. k.suzuki@ic.ac.uk
Murtuza
B
B
Smolenski
R T
RT
Sammut
I A
IA
Suzuki
N
N
Kaneda
Y
Y
Yacoub
M H
MH
D000818:Animals; D017690:Cell Transplantation / Q000379:methods*; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D015870:Gene Expression; D006334:Heart Function Tests / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D008297:Male; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation*; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D009204:Myocardial Revascularization / Q000379:methods; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D015996:Survival Rate; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors