Insulin-like growth factor-1 enhances the efficacy of myoblast transplantation with its multiple functions in the chronic myocardial infarction rat model.
BACKGROUND
Myoblast transplantation (Tx) is promising for the improvement of cardiac function in ischemic cardiomyopathy. Insulin-like growth factor-1 (IGF-1) has anti-apoptotic and angiogenic effects, and induces myocyte hypertrophy. Our hypothesis is that topical and slow-release IGF-1 enhances the efficacy of Tx through its multiple functions.


METHODS
Four weeks after coronary artery ligation, Lewis rats were divided into four groups: (1) IGF-1+Tx, injection of 6 x 10(6) myoblasts into the infarcted area with placement of an IGF-1-impregnated sheet on the left ventricular (LV) free wall; (2) Tx, Tx alone; (3) IGF-1, IGF-1 sheet alone; and (4) control. We measured cardiac function and performed immunohistochemical examinations.


RESULTS
At 4 weeks after treatment, LV diastolic dimension was the smallest, end-systolic elastance was the highest, and tau was the smallest in the IGF-1+Tx group. The graft volume in the IGF-1+Tx group was 3-fold larger than in the Tx group. One day after transplantation, TUNEL-positive donor cells were fewer in the IGF-1+Tx than in the Tx group. Western blot analysis demonstrated that the phosphorylation of Akt increased and the expression of Bax decreased in the transplanted area of IGF-1+Tx rats compared with Tx rats. The vascular density in the peri-infarcted area was larger in IGF-1+Tx than in Tx rats. The mean diameter of graft-derived myotubes was larger in IGF-1+Tx than in Tx animals.


CONCLUSIONS
IGF-1 increases the graft volume and enhances the efficacy of Tx in the chronic myocardial infarction model due to its multiple effects of preventing apoptosis, inducing angiogenesis, and promoting myoblast growth.
Kanemitsu
Naoki
N
Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Tambara
Keiichi
K
Premaratne
Goditha Upul
GU
Kimura
Yu
Y
Tomita
Shinji
S
Kawamura
Teruhisa
T
Hasegawa
Koji
K
Tabata
Yasuhiko
Y
Komeda
Masashi
M
D000287:Administration, Topical; D042501:Angiogenic Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D006328:Cardiac Catheterization; D002908:Chronic Disease; D003692:Delayed-Action Preparations; D003971:Diastole; D004452:Echocardiography; D004548:Elasticity; D006321:Heart / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology; D032446:Myoblasts / Q000637:transplantation*; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013599:Systole; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors
D042501:Angiogenic Proteins; D003692:Delayed-Action Preparations; D051028:bcl-2-Associated X Protein; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt