Varenne O, Pislaru S, Gillijns H, Van Pelt N, Gerard R D, Zoldhelyi P, Van de Werf F, Collen D, Janssens S P
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Belgium.
Circulation. 1998 Sep 1;98(9):919-26. doi: 10.1161/01.cir.98.9.919.
Nitric oxide, synthesized from L-arginine by nitric oxide synthase (NOS), is a vasodilator and inhibits vascular smooth muscle cell (SMC) proliferation and migration. The effects of local NOS gene transfer on restenosis after experimental balloon angioplasty were investigated.
Left anterior descending coronary artery angioplasty was performed in 25 pigs. Animals received an intramural injection of adenovirus (1.5 x 10(9) pfu) carrying either the NOS cDNA (AdCMVceNOS) or no cDNA (AdRR5) via the Infiltrator. Local gene transfer efficiency and bioactivity of recombinant protein were assessed after 4 days. Indices of restenosis were evaluated by computerized planimetry on coronary artery sections prepared 28 days after angioplasty. Adenoviral vectors permitted efficient gene delivery to medial SMCs and adventitial cells of coronary arteries. Vascular cGMP levels were depressed after angioplasty from 1.30+/-0.42 to 0.33+/-0.20 pmol/mg protein (P<0.05) but were restored after constitutive endothelial (ce) NOS gene transfer to 1.82+/-0.98 pmol/mg (P<0.05 versus injured group and P=NS versus control). The ratio of the neointimal area to the internal elastic lamina fracture length, maximal neointimal thickness, and percent stenosis were all reduced in AdCMVceNOS- versus AdRR5-transduced pigs (0.59+/-0.14 versus 0.80+/-0.19 mm, P=0.02; 0.75+/-0.21 versus 1.04+/-0.25 mm, P=0.019; and 53+/-15% versus 75+/-11%, P=0.006, respectively). Lumen area was significantly larger (0.70+/-0.35 mm2 in AdCMVceNOS versus 0.32+/-0.18 mm2 in AdRR5, P=0.007).
Percutaneous adenovirus-mediated NOS gene transfer resulted in efficient local overexpression of functional NOS after angioplasty in coronary arteries. Restored NO production in injured coronary arteries significantly reduced luminal narrowing, most likely through a combined effect on neointima formation and on vessel remodeling after angioplasty.
一氧化氮由一氧化氮合酶（NOS）催化L-精氨酸合成，是一种血管舒张剂，可抑制血管平滑肌细胞（SMC）的增殖和迁移。本研究旨在探讨局部NOS基因转移对实验性球囊血管成形术后再狭窄的影响。
对25头猪进行左前降支冠状动脉血管成形术。通过浸润针向动物冠状动脉壁内注射携带NOS cDNA（AdCMVceNOS）或不携带cDNA（AdRR5）的腺病毒（1.5×10⁹ pfu）。4天后评估局部基因转移效率和重组蛋白的生物活性。血管成形术后28天制备冠状动脉切片，通过计算机辅助平面测量法评估再狭窄指标。腺病毒载体可有效将基因传递至冠状动脉中膜SMC和外膜细胞。血管成形术后血管cGMP水平从1.30±0.42降至0.33±0.20 pmol/mg蛋白（P<0.05），但在组成型内皮（ce）NOS基因转移后恢复至1.82±0.98 pmol/mg（与损伤组相比P<0.05，与对照组相比P=无显著差异）。AdCMVceNOS转导的猪与AdRR5转导的猪相比，新生内膜面积与内弹力膜断裂长度之比、最大新生内膜厚度和狭窄百分比均降低（分别为0.59±0.14对0.80±0.19 mm，P=0.02；0.75±0.21对1.04±0.25 mm，P=0.019；53±15%对75±11%，P=0.006）。管腔面积显著更大（AdCMVceNOS组为0.70±0.35 mm²，AdRR5组为0.32±0.18 mm²，P=0.007）。
经皮腺病毒介导的NOS基因转移导致血管成形术后冠状动脉中功能性NOS的有效局部过表达。损伤冠状动脉中恢复的NO生成显著减少管腔狭窄，最可能是通过对新生内膜形成和血管成形术后血管重塑的联合作用实现的。
