Gene therapy for chronic myocardial ischemia using platelet-derived endothelial cell growth factor in dogs.
Platelet-derived endothelial cell growth factor (PD-ECGF), also known as thymidine phosphorylase (TP), has been reported to possess angiogenic activity and to inhibit apoptosis. This study was performed to determine whether PD-ECGF/TP can be used to ameliorate chronic myocardial ischemia. Myocardial ischemia was created in 40 mongrel dogs by placement of an ameroid constrictor on the proximal left anterior descending coronary artery (LAD). Plasmid vector encoding human PD-ECGF/TP cDNA (pCIhTP group; n = 12), empty vector pCI (pCI group; n = 12), or saline (Saline group; n = 12) was directly injected into the LAD territory 3 wk after ameroid constrictor implantation. Myocardial blood flow was detected using PET at baseline, 3 wk after ameroid constrictor implantation, and 2 wk after therapeutic treatment. At the end of the experiment, the hearts were isolated for biological and histological analysis. In the pCIhTP group, the transfected heart strongly expressed PD-ECGF/TP. The size of the infarct was smaller in the pCIhTP group than in the pCI or Saline group. The number of apoptotic myocardial cells was decreased in the pCIhTP group compared with the control groups based on triple immunohistochemical staining for von Willebrand factor, alpha-actin smooth muscle cells, and single-strand DNA. The level of proapoptotic protein Bax markedly decreased in the pCIhTP group compared with the other groups. Double immunohistochemical staining for von Willebrand factor and alpha-actin smooth muscle cells demonstrated that angiogenesis and arteriogenesis occurred, and paralleled the changes in myocardial blood flow and myocardial function in the pCIhTP group. We conclude that genetic approaches using PD-ECGF/TP to target the myocardium are effective for alleviating chronic myocardial ischemia.
Li
Wei
W
Second Department of Surgery, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki, Matsuoka-Cho, Yoshida-Gun, Fukui 9101193, Japan.
Tanaka
Kuniyoshi
K
Ihaya
Akio
A
Fujibayashi
Yasuhisa
Y
Takamatsu
Shinji
S
Morioka
Kouichi
K
Sasaki
Masato
M
Uesaka
Takahiko
T
Kimura
Tetsuya
T
Yamada
Narihisa
N
Tsuda
Takeshi
T
Chiba
Yukio
Y
D000818:Animals; D017209:Apoptosis; D002908:Chronic Disease; D003326:Coronary Circulation; D004285:Dogs; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006321:Heart / Q000503:physiopathology; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D018919:Neovascularization, Physiologic; D010957:Plasmids; D051381:Rats; D013939:Thymidine Phosphorylase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D013939:Thymidine Phosphorylase