轉染單純皰疹病毒胸苷激酶基因抑制移植靜脈內膜增生_《中國普外基礎與臨床雜志》

作者：

羅濤 ¹ , 張強 ² , 張建 ¹ , 李建新 ¹

1.首都醫科大學宣武醫院血管外科(北京100053);;
2.中國醫科大學附屬第一臨床醫院干診病房（沈陽110001）;

關鍵詞：

移植靜脈基因內膜增生

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目的　探討腺病毒載體轉染單純皰疹病毒胸苷激酶(herpes simplex virus thymidine kinase，HSVtk)基因對移植靜脈內膜增生的作用。
方法　用Wistar大鼠建立自體靜脈移植模型。以載有HSVtk(4×109 plaque forming units)基因的腺病毒孵育頸靜脈，將靜脈倒置移植于腎下腹主動脈。從移植術后第3 d開始腹腔注射丙氧鳥苷〔ganciclovir,GCV，60 mg/(kg·d)，2次/d〕共21 d，取出移植靜脈標本后用PCR法檢測HSVtk基因的表達，用原位雜交法檢測基因的轉錄；進行彈力纖維染色及增殖細胞核抗原(PCNA)免疫組化染色，觀察內膜增生及平滑肌細胞增殖；用TUNEL法觀察移植靜脈平滑肌細胞凋亡情況。
結果　移植靜脈內膜進行性增厚，新生內膜中有大量增殖狀態的平滑肌細胞。移植后第3 d，轉染HSVtk基因的靜脈經PCR擴增出590 bp陽性條帶，HSVtk基因開始表達mRNA。HSVtk/GCV對靜脈內膜增生有明顯抑制作用，而單獨予以HSVtk對內膜增生無影響〔(17.2±3.2) μm vs (31.1±2.5) μm, P＜0.05〕。HSVtk/GCV使靜脈中平滑肌細胞增殖指數下降為(9.1±2.3)%，凋亡細胞指數升高到(28.7±3.6)%，分別于空白對照組〔(38.7±5.6)%,(18.5±2.6)%〕相比差異均有統計學意義(P＜0.05)。
結論　HSVtk/GCV系統通過抑制平滑肌細胞增殖及促進細胞凋亡抑制移植靜脈內膜增生。

引用本文： 羅濤,張強,張建,李建新. 轉染單純皰疹病毒胸苷激酶基因抑制移植靜脈內膜增生. 中國普外基礎與臨床雜志, 2008, 15(10): 743-747. doi: 復制

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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.	羅濤，張強，張建, 等. 早期炎性反應對移植靜脈中外源基因表達效率的影響 [Ｊ]. 中國普通外科雜志, 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.	羅濤，張強，張建, 等. 腺病毒介導胸苷激酶基因對靜脈平滑肌細胞增殖及內膜增生抑制作用的研究 [Ｊ]. 中國普外基礎與臨床雜志, 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. 　羅濤，張強，張建, 等. 早期炎性反應對移植靜脈中外源基因表達效率的影響 [Ｊ]. 中國普通外科雜志, 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. 　羅濤，張強，張建, 等. 腺病毒介導胸苷激酶基因對靜脈平滑肌細胞增殖及內膜增生抑制作用的研究 [Ｊ]. 中國普外基礎與臨床雜志, 2006; 13(3)∶291.

《中國普外基礎與臨床雜志》

轉染單純皰疹病毒胸苷激酶基因抑制移植靜脈內膜增生

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《中國普外基礎與臨床雜志》

轉染單純皰疹病毒胸苷激酶基因抑制移植靜脈內膜增生

摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

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