Hilker Michael, Längin Tina, Hake Ulrich, Schmid Franz-Xaver, Kuroczynski Wlodzimierz, Lehr Hans-Anton, Oelert Helmut, Buerke Michael
Department of Thoracic and Cardiovascular Surgery, Johannes Gutenberg University, Mainz, Germany.
Eur J Cardiothorac Surg. 2003 Apr;23(4):620-5. doi: 10.1016/s1010-7940(03)00017-4.
Aorto-coronary bypass graft disease with its increasing clinical signification represents an unsolved problem in cardiological and heart surgery practice. Late occlusion of autologous saphenous vein grafts is due to medial and neointimal thickening secondary to migration and proliferation of smooth muscle cells (SMCs) and the subsequent formation of atherosclerotic plaques. This study is aimed at identifying differentially expressed genes in human stenotic bypass grafts to detect unknown pathomechanism and to identify novel targets for prophylactic treatment options.
Stenotic saphenous aorto-coronary bypass grafts (n=5) were retrieved during re-do aorto-coronary bypass surgery. Ungrafted saphenous vein segments (n=5) were taken from the same group of patients and served as internal controls. cDNA samples were prepared and hybridized to cDNA arrays.
Some of the differentially expressed genes complied with expected gene expression including upregulation of c-jun and CDK10. In addition, previously unidentified gene expression patterns were detected such as upregulation of HSP70, fibronectin1, erbB3 proto-oncogene and c-myc. To confirm the latter finding, upregulation of c-myc in neointimal and medial SMCs of stenotic graft segments was confirmed by in situ hybridization studies and by immunohistochemistry.
Gene expression patterns of human stenotic bypass grafts retrieved by re-do operations can be reliably analyzed by cDNA array technology. With this technique, new therapeutic targets in patients could be identified as shown by the findings regarding c-myc. c-myc is a proto-oncogene acting as a transcription factor and blocking c-myc has shown a reduction of neointima formation in animal models. Our study yields a rational for the use of antisense c-myc oligonucleotides to reduce neointima formation and to avoid stenosis in patients.
随着临床意义的不断增加，主动脉-冠状动脉旁路移植血管疾病在心脏病学和心脏外科实践中仍是一个未解决的问题。自体大隐静脉移植血管的晚期闭塞是由于平滑肌细胞（SMC）迁移和增殖继发的中膜和内膜增厚以及随后动脉粥样硬化斑块的形成。本研究旨在鉴定人类狭窄旁路移植血管中差异表达的基因，以检测未知的发病机制并确定预防性治疗方案的新靶点。
在再次进行主动脉-冠状动脉旁路手术期间获取狭窄的大隐静脉主动脉-冠状动脉旁路移植血管（n = 5）。未移植的大隐静脉段（n = 5）取自同一组患者并用作内部对照。制备cDNA样品并与cDNA阵列杂交。
一些差异表达的基因符合预期的基因表达，包括c-jun和CDK10的上调。此外，还检测到以前未鉴定的基因表达模式，如HSP70、纤连蛋白1、erbB3原癌基因和c-myc的上调。为证实后一发现，通过原位杂交研究和免疫组织化学证实了狭窄移植血管段的内膜和中膜SMC中c-myc的上调。
通过再次手术获取的人类狭窄旁路移植血管的基因表达模式可通过cDNA阵列技术可靠地分析。利用该技术，可以确定患者的新治疗靶点，如关于c-myc的研究结果所示。c-myc是一种作为转录因子的原癌基因，在动物模型中阻断c-myc已显示内膜增生减少。我们的研究为使用反义c-myc寡核苷酸减少内膜增生并避免患者出现狭窄提供了理论依据。
