Gene transfer of endothelial nitric oxide synthase improves relaxation of carotid arteries from diabetic rabbits
Gene transfer of endothelial nitric oxide synthase improves relaxation of carotid arteries from diabetic rabbits
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DOI：
10.1161/01.cir.101.9.1027
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发表时间：
2000-03-07
期刊：
影响因子：
37.8
通讯作者：
Heistad, DD
中科院分区：
文献类型：
--
作者：
Lund, DD;Faraci, FM;Heistad, DD
背景：糖尿病与一氧化氮介导的血管舒张损伤有关。本研究的目的是确定腺病毒介导的内皮NO合成酶（eNOS）或Cu/Zn超氧化物歧化酶（SOD1）的基因转移是否能改善四氧嘧啶诱导的糖尿病家兔对乙酰胆碱的反应性。方法与结果：8周后，糖尿病家兔血浆葡萄糖（418+/-135 mg/dL）（平均+/-SEM）高于正常家兔（105+/-4 mg/dL）。切除颈动脉，切成环形段。动脉与表达β -半乳糖苷酶（β -gal）、eNOS、SOD1或载体的CMV启动子驱动的腺病毒载体孵育2小时。与病毒孵育后，动脉再孵育24小时以允许转基因表达。血管反应性通过记录等长张力来检测。在用苯肾上腺素预收缩后，糖尿病和正常动脉对内皮非依赖性血管扩张剂硝普钠的反应相似。内皮依赖性乙酰胆碱弛缓（3 × 10(-6) mol/L）在糖尿病动物动脉中（68+/-5%）明显低于正常血管（90+/-3%）。腺病毒转染eNOS动脉改善了糖尿病患者对乙酰胆碱的舒张反应(EC50 eNOS = 0.64 +/- 0.12 X 10(-7) mol/L，对照组= 1.70 +/- 0.43 X 10(-7) mol/L)，但对正常动脉没有影响。100 μ mol/L n - ω -硝基-L-精氨酸可抑制各组对乙酰胆碱反应的血管松弛。基因转染SOD1或P-gal后，糖尿病或正常家兔动脉对乙酰胆碱的反应没有变化。结论：腺病毒介导的eNOS基因转移可改善糖尿病家兔一氧化氮介导的血管舒张功能，而非SOD。
Background-Diabetes mellitus is associated with impairment of NO-mediated vascular relaxation. The purpose of this study was to determine whether adenovirus-mediated gene transfer of endothelial NO synthase (eNOS) or Cu/Zn superoxide dismutase (SOD1) improves responsiveness to acetylcholine in alloxan-induced diabetic rabbits.Methods and Results-After 8 weeks, plasma glucose was greater in diabetic rabbits (418+/-135 mg/dL) (mean+/-SEM) than in normal rabbits (105+/-4 mg/dL). Carotid arteries were removed and cut into ring segments. Arteries were incubated for 2 hours with adenoviral vectors driven by a CMV promoter expressing beta-galactosidase (beta-gal), eNOS, SOD1, or vehicle. After incubation with virus, arteries were incubated for an additional 24 hours to allow transgene expression. Vascular reactivity was examined by recording isometric tension. After precontraction with phenylephrine, responses to the endothelium-independent vasodilator sodium nitroprusside were similar in diabetic and normal arteries. Endothelium-dependent relaxation to acetylcholine (3 X 10(-6) mol/L) was significantly less in arteries from diabetic animals (68+/-5%) than in normal vessels (90+/-3%). Adenoviral transfection of arteries with eNOS improved relaxation in response to acetylcholine in diabetic (EC50 eNOS = 0.64 +/- 0.12 X 10(-7) mol/L versus vehicle = 1.70 +/- 0.43 x 10(-7) mol/L) but not normal arteries. Vasorelaxation in response to acetylcholine was inhibited by N-omega-nitro-L-arginine (100 mu mol/L) in all groups. Responses to acetylcholine were unchanged after gene transfection of SOD1 or P-gal in arteries from diabetic or normal rabbits.Conclusions-Adenovirus-mediated gene transfer of eNOS, but not SOD, improves impaired NO-mediated relaxation in vessels from diabetic rabbits.