Effects of adenovirus-mediated transfer of C-type natriuretic peptide gene on arterialized vein graft.

腺病毒介导的C型利钠肽基因转移对动脉化静脉移植物的影响。

• 批准号: 12671154
• 负责人: IKEDA Tadashi
• 金额: $ 2.18万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671154/
• 关键词: CABG; atherosclerosis; vein graft; gene transfer; adenovirus; natriuretic peptide; アデノウイルス; 遺伝子治療; C型ナトリウム利尿ペプチド

We previously reported that C-type natriuretic peptide (CNP) occurs in vascular endothelial cells and acts toward relaxation and growth inhibition of smooth muscle cell. The aim of this study was to overexpress CNP by adenovirus-mediated gene transfer in proliferative vascular lesions and investigate its effects on vascular remodeling in vivo. Replication-deficient adenoviral vectors encoding CNP gene (Ad.CNP) and E.coli LacZ gene (Ad.LacZ) were developed by conventional method.1. After the femoral artery of male Japanese White rabbits was injured by balloon catheter, Ad.CNP or Ad.LacZ was instilled in the vascular lumen for 30 minutes. Two weeks later, neointimal formation after balloon injury was significantly suppressed in CNP group compared with LacZ group. In CNP group, CNP staining was more intense than in LacZ group and expression of SM-2, which is the molecular marker of well-differentiated SMCs, was induced in the residual neointima. Angiotensin II caused more potent vasoconstriction in CNP group than in LacZ group. Evans blue dye staining revealed accelerated reendothelialization in CNP group and acetylcholine caused more potent relaxation in CNP group than in LacZ group.2. Autologous rabbit jugular vein grafts were incubated ex vivo in a solution of Ad.CNP or Ad.LacZ and then interposed in the carotid artery. Reendothelialization, mural thrombi formation, and intima/media ratio were evaluated on the 14th and 28th postoperative days. More reendothelialization was seen in Ad.CNP-infected grafts than in Ad.LacZ-infected grafts. The mural thrombus area was smaller in Ad.CNP group than in Ad.LacZ group. Neointimal thickening was significantly suppressed in the Ad.CNP group.

我们先前报道，C型利钠肽(CNP)存在于血管内皮细胞中，对血管内皮细胞具有松弛和抑制生长的作用。本研究的目的是通过腺病毒介导的基因转移在增生性血管病变中过表达CNP，并探讨其在体内血管重塑中的作用。用常规方法构建携带CNP基因(Ad.CNP)和E.ColiLacZ基因(Ad.LacZ)的复制缺陷腺病毒载体。用球囊导管损伤雄性日本大白兔股动脉后，分别在管腔内注入CNP或LacZ 30min。2周后，与LacZ组相比，CNP组球囊损伤后新生内膜的形成明显减少。CNP组CNP染色较LacZ组强，残留新生内膜中可诱导分化良好的SMC分子标志物SM-2的表达。血管紧张素II在CNP组引起的血管收缩作用比LacZ组更强。结果：1.伊文思蓝染色显示CNP组血管内皮化加速，乙酰胆碱松弛作用强于LacZ组。自体兔颈静脉移植物在体外孵育于Ad.CNP或Ad.LacZ的溶液中，然后插入颈动脉。分别于术后第14天和第28天检测血管内皮化、壁血栓形成、内膜/中膜比值。Ad.CNP感染的移植物比Ad.LacZ感染的移植物有更多的再内皮化。Ad.CNP组的壁血栓面积小于Ad.LacZ组。Ad.CNP组新生内膜增厚明显受到抑制。

项目成果

K.Doi: "C-type natriuretic peptide induces redifferentiation of vascular smooth muscle cells with accelerated reendothelialization"Arterioscler Thromb Vasc Biol. 21. 930-936 (2001)

K.Doi：“C 型利钠肽通过加速再内皮化诱导血管平滑肌细胞的再分化”Arterioscler Thromb Vasc Biol。

K. Doi, et al.: "C-type natriuretic peptide induces re-differentiation of vascular smooth muscle cells with accelerated re-endothelialization"Arterioscler. Thromb. Vasc. Biol.. 21. 930-936 (2001)

K. Doi 等人：“C 型利钠肽诱导血管平滑肌细胞的再分化，加速再内皮化”Arterioscler。

Kentaro Doi,Tadashi Ikeda Hiroshi Itoh 他: "C-type natriuretic peptide induces re-differentiation of vascular smooth muscle cells with accelerated re-endothelin"Arteriosclerosis,Thrombosis and Vascular Biology. (in press).

Kentaro Doi、Tadashi Ikeda Hiroshi Itoh 等人：“C 型利钠肽通过加速再内皮素诱导血管平滑肌细胞的再分化”动脉硬化、血栓形成和血管生物学（正在出版）。

N. Ohno et al.: "Accelerated reendothelialization with suppressed thrombogenic property and neointimal hyperplasia of rabbit jugular vein grafts by adenovirus-mediated gene transfer of C-type natriuretic peptide"Circulation. 105(in press). (2002)

N. Ohno 等人：“通过腺病毒介导的 C 型钠尿肽基因转移，加速再内皮化，抑制兔颈静脉移植物的血栓形成特性和新生内膜增生”循环。

K.Doi: "C-type natriuretic peptide induces redifferentiation of vascular smooth muscle cells with accelerated reendothelialization"Arterioscler Thromb Vasc. Biol.. 21. 930-936 (2001)

K.Doi：“C 型利钠肽诱导血管平滑肌细胞再分化，加速再内皮化”Arterioscler Thromb Vasc。