Retrovirus-Mediated Herpes Simplex Virus Thymidine Kinase Gene Therapy for the Prevention of Stenosis in Rat Carotid Artery Injury Model.
10.4070/kcj.1998.28.6.977
- Author:
Dong Woon KIM
;
Young Gyu KIM
;
Tae Geun OH
;
Myeong Chan CHO
;
Seung Taik KIM
- Publication Type:Original Article
- Keywords:
Gene therapy;
Restenosis;
HSVtk gene
- MeSH:
Angiography;
Animals;
Carotid Arteries*;
Carotid Artery Injuries*;
Cell Death;
Constriction, Pathologic*;
DNA;
DNA, Complementary;
Ganciclovir;
Genetic Therapy*;
Gravitation;
Herpes Simplex*;
Hyperplasia;
Myocytes, Smooth Muscle;
Phenobarbital;
Phosphotransferases*;
Rats*;
Simplexvirus*;
Thymidine Kinase;
Zidovudine
- From:Korean Circulation Journal
1998;28(6):977-989
- CountryRepublic of Korea
- Language:Korean
-
Abstract:
BACKGROUND: Herpes simplex virus thymidine kinase (HSVtk) phosphorylates the prodrug ganciclovir to a nucleoside analog that inhibits DNA synthesis, causing cell death. Neighbouring nontransfected cells may be affected through a 'bystander effect', thereby amplifying the antiproliferative actions. This study was carried out to determine whether retrovirus-mediated HSVtk gene therapy could reduce intimal hyperplasia and prevent stenosis following balloon injury of the rat carotid artery. METHODS: A replication-defective recombinant retroviral vector containing HSVtk cDNA (LtkSN) was constructed. Cultured primary rat smooth muscle cells (SMCs) infected with this vector (SMC/LtkSN) were transplanted to the balloon injured rat right carotid artery. One week after transplantation, HSVtk gene therapy group was administered a 2-week treatment of ganciclovir (30 mg/kg/d). Three weeks after balloon injury and SMC/LtkSN transplantation, carotid arteriography was performed and carotid arteries were perfusion-fixed for histologic examination. RESULTS: Carotid arteriographic evaluation comparing with the uninjured left carotid artery showed that the mean luminal diameter of HSVtk gene therapy group (n=5, 85+/-3%) was significantly larger than that of balloon injury only group (n=5, 65+/-5%). The neointimal mass of HSVtk gene therapy group was less than that of balloon injury only group. SMC/LtkSN transplantation without ganciclovir treatment group (n=3) showed asymmetric intimal proliferation probably because of gravitational pooling of seeding. There were inflammatory cell infiltrations at the gravity dependent portion of HSVtk gene therapy group. CONCLUSION: Retrovirus-mediated HSVtk gene therapy following balloon injury of the rat carotid artery reduced neointimal expansion and arteriographic stenosis.
