Mann M J, Gibbons G H, Kernoff R S, Diet F P, Tsao P S, Cooke J P, Kaneda Y, Dzau V J
Division of Cardiovascular Medicine, Falk Cardiovascular Research Center, Stanford University School of Medicine, CA 94305, USA.
Proc Natl Acad Sci U S A. 1995 May 9;92(10):4502-6. doi: 10.1073/pnas.92.10.4502.
Previously, researchers have speculated that genetic engineering can improve the long-term function of vascular grafts which are prone to atherosclerosis and occlusion. In this study, we demonstrated that an intraoperative gene therapy approach using antisense oligodeoxynucleotide blockage of medial smooth muscle cell proliferation can prevent the accelerated atherosclerosis that is responsible for autologous vein graft failure. Selective blockade of the expression of genes for two cell cycle regulatory proteins, proliferating cell nuclear antigen and cell division cycle 2 kinase, was achieved in the smooth muscle cells of rabbit jugular veins grafted into the carotid arteries. This alteration of gene expression successfully redirected vein graft biology away from neointimal hyperplasia and toward medial hypertrophy, yielding conduits that more closely resembled normal arteries. More importantly, these genetically engineered grafts proved resistant to diet-induced atherosclerosis. These findings establish the feasibility of developing genetically engineered bioprostheses that are resistant to failure and better suited to the long-term treatment of occlusive vascular disease.
此前，研究人员推测基因工程可以改善易于发生动脉粥样硬化和闭塞的血管移植物的长期功能。在本研究中，我们证明了一种术中基因治疗方法，即使用反义寡脱氧核苷酸阻断中膜平滑肌细胞增殖，可以预防导致自体静脉移植物失败的加速动脉粥样硬化。在移植到颈动脉的兔颈静脉平滑肌细胞中，实现了对两种细胞周期调节蛋白（增殖细胞核抗原和细胞分裂周期2激酶）基因表达的选择性阻断。这种基因表达的改变成功地使静脉移植物生物学从内膜增生转向中膜肥厚，产生了更类似于正常动脉的管道。更重要的是，这些基因工程移植物被证明对饮食诱导的动脉粥样硬化具有抗性。这些发现确立了开发抗失败且更适合长期治疗闭塞性血管疾病的基因工程生物假体的可行性。
