Adenovirus Vector Mediated Transfer of Human Herpes Simplex Virus Thymidine Kinase Gene Inhibit Intimal Hyperplasia of Vein Grafts_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LUO Tao ¹ , ZHANG Qiang ² , ZHANG Jian ¹ , LI Jianxin ¹

1.Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China;;
2.Department of Senior Officials Inpatient Ward, The First Clinical Hospital, China Medical University, Shenyang 110001, ChinaCorresponding Author: LUO Tao, E-mail: doctorluo@yahoo.cn;

Corresponding author：

Keywords：

Vein graft; Gene; Intimal hyperplasia

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Objective 　To investigate the effect of adenovirus vector mediated transfer of human herpes simplex virus thymidine kinase (HSVtk) gene inhibits intimal hyperplasia of vein grafts. 　
Methods 　Auto vein graft models of Wistar rats were established. Adenovirus vector dwelled in cervical veins which were transplanted into inferior renal abdominal aorta. The combination of HSVtk (4×109 plaque forming units) and ganciclovir (GCV) was applied to test the inhibition effect. GCV was infused 〔60 mg/(kg·d), IP, Bid〕 from day 3 to day 21 after transplantation. Vein samples were harvested and the existence of HSVtk DNA was measured by PCR and the mRNA of it was studied by in situ hybridization. Van gieson (VG) and proliferating cell nuclear antigen (PCNA) stains were carried out in paraffin sections to study the thickness of neointima and smooth muscle cells (SMCs) proliferation with a computer-assisted analysis system. The apoptosis of SMCs also was detected by TUNEL.
Results 　The existence of HSVtk gene in veins and its transcription were demonstrated. Morphometric analysis demonstrated a reduced intima thickness in the group receiving combination therapy (HSVtk/GCV) compared with HSVtk alone 〔(17.2±3.2) μm versus (31.1±2.5) μm, P＜0.05〕. GCV per se had no effect on intimal hyperplasia after vein transplantation. The apoptosis of SMCs increased significantly and expression of PCNA decreased in HSVtk/GCV gene therapy group versus blank control group 〔(9.1±2.3)% vs (28.7±3.6)%, P＜0.05; (38.7±5.6)%vs (18.5±2.6)%, P＜0.05〕.
Conclusion 　GCV conditions reduction of intimal hyperplasia after intraluminal delivery of HSVtk in transplanting vena veins involving SMCs apoptosis.

Citation： LUO Tao,ZHANG Qiang,ZHANG Jian,LI Jianxin. Adenovirus Vector Mediated Transfer of Human Herpes Simplex Virus Thymidine Kinase Gene Inhibit Intimal Hyperplasia of Vein Grafts. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2008, 15(10): 743-747. doi: Copy

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14.	罗涛，张强，张建, 等. 早期炎性反应对移植静脉中外源基因表达效率的影响 [Ｊ]. 中国普通外科杂志, 2006; 15(5)∶349.
15.	Sandalon Z, Fusenig NE, McCutcheon J, et al. Suicide gene therapy for premalignant disease: a new strategy for the treatment of intraepithelial neoplasia [Ｊ]. Gene Ther, 2001; 8(3)∶232.
16.	Burrows FJ, Gore M, Smiley WR, et al. Purified herpes simplex virus thymidine kinase retroviral particles: Ⅲ. Characterization of bystander killing mechanisms in transfected tumor cells [Ｊ]. Cancer Gene Ther, 2002; 9(1)∶87.
17.	Nicholas TW, Read SB, Burrows FJ, et al. Suicide gene therapy with herpes simplex virus thymidine kinase and ganciclovir is enhanced with connexins to improve gap junctions and bystander effects [Ｊ]. Histol Histopathol, 2003; 18(2)∶495.
18.	罗涛，张强，张建, 等. 腺病毒介导胸苷激酶基因对静脉平滑肌细胞增殖及内膜增生抑制作用的研究 [Ｊ]. 中国普外基础与临床杂志, 2006; 13(3)∶291.

1. 　Chandiwal A, Balasubramanian V, Baldwin ZK, et al. Gene therapy for the extension of vein graft patency: a review [Ｊ]. Vasc Endovascular Surg, 2005; 39(1)∶1.
2. 　Appleby CE, Kingston PA. Gene therapy for restenosis——what now, what next? [Ｊ]. Curr Gene Ther, 2004; 4(2)∶153.
3. 　Izzat MB, West RR, Bryan AJ, et al. Coronary artery bypass surgery: current practice in the United Kingdom [Ｊ]. Br Heart J, 1994; 71(4)∶382.
4. 　Zou Y, Dietrich H, Hu Y, et al. Mouse model of venous bypass graft arteriosclerosis [Ｊ]. Am J Pathol, 1998; 153(4)∶1301.
5. 　Stark VK, Hoch JR, Warner TF, et al. Monocyte chemotactic protein-1 expression is associated with the development of vein graft intimal hyperplasia [Ｊ]. Arterioscler Thromb Vasc Biol, 1997; 17(8)∶1614.
6. 　Greco O, Dachs GU. Gene directed enzyme/prodrug therapy of cancer: historical appraisal and future prospectives [Ｊ]. J Cell Physiol, 2001; 187(1)∶22.
7. 　TyynelK, Sandmair AM, Turunen M, et al. Adenovirus-mediated herpes simplex virus thymidine kinase gene therapy in BT4C rat glioma model [Ｊ]. Cancer Gene Ther, 2002; 9(11)∶917.
8. 　Chang MW, Ohno T, Gordon D, et al. Adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene inhibits vascular smooth muscle cell proliferation and neointima formation following balloon angioplasty of the rat carotid artery [Ｊ]. Mol Med, 1995; 1(2)∶172.
9. 　Steg PG, Tahlil O, Aubailly N, et al. Reduction of restenosis after angioplasty in an atheromatous rabbit model by suicide gene therapy [Ｊ]. Circulation, 1997; 96(2)∶408.
10. 　Eslami MH, Gangadharan SP, Sui X, et al. Gene delivery to in situ veins: differential effects of adenovirus and adeno-associated viral vectors [Ｊ]. J Vasc Surg, 2000; 31(6)∶1149.
11. 　Baker AH, Mehta D, George SJ, et al. Prevention of vein graft failure: potential applications for gene therapy [Ｊ]. Cardiovasc Res, 1997; 35(3)∶442.
12. 　Ander S, MacLennan M, Bentil S, et al. Pressure-induced vector transport in human saphenous vein [Ｊ]. Ann Biomed Eng, 2005; 33(2)∶202.
13. 　Rekhter MD, Shah N, Simari RD, et al. Graft permeabilization facilitates gene therapy of transplant arteriosclerosis in a rabbit model [Ｊ]. Circulation, 1998; 98(13)∶1335.
14. 　罗涛，张强，张建, 等. 早期炎性反应对移植静脉中外源基因表达效率的影响 [Ｊ]. 中国普通外科杂志, 2006; 15(5)∶349.
15. 　Sandalon Z, Fusenig NE, McCutcheon J, et al. Suicide gene therapy for premalignant disease: a new strategy for the treatment of intraepithelial neoplasia [Ｊ]. Gene Ther, 2001; 8(3)∶232.
16. 　Burrows FJ, Gore M, Smiley WR, et al. Purified herpes simplex virus thymidine kinase retroviral particles: Ⅲ. Characterization of bystander killing mechanisms in transfected tumor cells [Ｊ]. Cancer Gene Ther, 2002; 9(1)∶87.
17. 　Nicholas TW, Read SB, Burrows FJ, et al. Suicide gene therapy with herpes simplex virus thymidine kinase and ganciclovir is enhanced with connexins to improve gap junctions and bystander effects [Ｊ]. Histol Histopathol, 2003; 18(2)∶495.
18. 　罗涛，张强，张建, 等. 腺病毒介导胸苷激酶基因对静脉平滑肌细胞增殖及内膜增生抑制作用的研究 [Ｊ]. 中国普外基础与临床杂志, 2006; 13(3)∶291.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Adenovirus Vector Mediated Transfer of Human Herpes Simplex Virus Thymidine Kinase Gene Inhibit Intimal Hyperplasia of Vein Grafts

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