Long-term effect of gene therapy for chronic ischemic myocardium using platelet-derived endothelial cell growth factor in dogs.
BACKGROUND
We previously reported the 2-week benefits of platelet-derived endothelial cell growth factor (PD-ECGF) gene therapy in chronically ischemic myocardium. However, the long-term effects and safety using this gene have not been reported.


METHODS
Chronic myocardial ischemia was created in 24 dogs by stenosing the origin of the left anterior descending coronary artery (LAD) using an ameroid constrictor. Two weeks later, the PD-ECGF gene, the LacZ gene, or saline was infused directly into the myocardium in the LAD area. The myocardial blood volume and myocardial function were examined prior to ischemia, immediately before gene injection, and for 6 months following injection, and then the organs were harvested for histological and molecular examination.


RESULTS
PD-ECGF gene treatment significantly attenuated endocardial infarction at 6 months. Myocardial blood volume and myocardial function decreased in all three groups after ameroid implantation, but recovered after 2 weeks in the PD-ECGF-treated group, and maintained a higher level of function during the examination period. Histological analysis demonstrated that angiogenesis and arteriogenesis occurred after PD-ECGF gene treatment. There was a decreased expression of the pro-apoptotic proteins, active caspase-3 and Bax, and the number of apoptotic myocardial cells was lower in the PD-ECGF-treated group. Histological examination demonstrated that no abnormal histological changes or neoplasms were found in any organs.


CONCLUSIONS
We conclude that gene targeting of ischemic myocardium using PD-ECGF generated long-term improvement in cardiac function by causing angiogenesis, arteriogenesis and inhibiting apoptosis, but did not induce neoplasms in the remote organs, and may be a promising therapy.
Li
Wei
W
Second Department of Surgery, Faculty of Medical Sciences, University of Fukui, Fukui, Japan. liw4@ccf.org
Tanaka
Kuniyoshi
K
Morioka
Koichi
K
Takamori
Atsushi
A
Handa
Mitsuteru
M
Yamada
Narihisa
N
Ihaya
Akio
A
D000818:Animals; D017209:Apoptosis; D002908:Chronic Disease; D003326:Coronary Circulation; D004285:Dogs; D015316:Genetic Therapy; D005822:Genetic Vectors; D006321:Heart / Q000503:physiopathology; D006801:Humans; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology; D018919:Neovascularization, Physiologic; D010957:Plasmids; D013939:Thymidine Phosphorylase / Q000235:genetics*; D019076:Transgenes; D016896:Treatment Outcome
D013939:Thymidine Phosphorylase