Huynh T T, Davies M G, Barber L, Svendsen E, Hagen P O
Vascular Biology and Atherosclerosis Research Laboratory, Duke University Medical Center, Durham, North Carolina, 27710, USA.
J Surg Res. 1998 Jul 1;77(2):104-11. doi: 10.1006/jsre.1998.5300.
Intimal hyperplasia is due to the migration and proliferation of vascular smooth muscle cells after bypass surgery. Tyrosine kinases are involved in many signal transduction pathways including cell proliferation. This study examines the effects of local treatment with the tyrosine kinase inhibitor, tyrphostin AG-51, on the formation of intimal hyperplasia in vein grafts.
Thirty-nine New Zealand White rabbits underwent interposition bypass grafting of the carotid artery using the jugular vein. In the first group (TKI), tyrphostin AG-51 (5 mg), dissolved in 600 microliter of dimethyl sulfoxide and Ringer's lactate (2:1, v:v), was used to incubate the veins ex vivo prior to grafting and delivered locally in 2.5 ml of 30% pluronic gel after grafting. The second group (DMSO) received the same treatment but without tyrphostin. In the third group (control), tyrphostin and DMSO were omitted from the incubation and gel delivery solutions. Postoperatively, vein grafts were harvested on Day 3 for Western analysis using an antiphosphotyrosine antibody (PY-20) to assess for tyrosine kinase activity, and on Day 28 for either morphologic or contractile function studies.
Local application of the TKI to vein grafts resulted in a 49% reduction in intimal hyperplasia compared to DMSO-treated vein grafts (31 +/- 4 micrometer vs. 61 +/- 5 micrometer, P < 0.01). Treatment with DMSO alone reduced intimal hyperplasia by 28% compared to control (85 +/- 4 micrometer, P < 0.05). The contractile responses in the DMSO and TKI-treated vein grafts were equivalent. Western analysis showed a 39-fold decrease in tyrosine phosphorylation with TKI treatment compared to control.
This study demonstrates that local short-term treatment with TKI produces a 49% reduction in intimal hyperplasia and suggests that phosphorylation of tyrosine residues is involved in the signaling pathways leading to the development of intimal hyperplasia in vein grafts.
内膜增生是旁路手术后血管平滑肌细胞迁移和增殖所致。酪氨酸激酶参与包括细胞增殖在内的多种信号转导途径。本研究检测酪氨酸激酶抑制剂 tyrphostin AG - 51 局部治疗对静脉移植物内膜增生形成的影响。
39 只新西兰白兔接受了使用颈静脉进行的颈动脉间置旁路移植术。在第一组（TKI）中，将溶解于 600 微升二甲基亚砜和乳酸林格氏液（2:1，v:v）中的 tyrphostin AG - 51（5 毫克）在移植前对静脉进行离体孵育，并在移植后以 2.5 毫升 30%的普朗尼克凝胶局部给药。第二组（DMSO）接受相同处理，但不含 tyrphostin。第三组（对照组）在孵育液和凝胶给药溶液中省略 tyrphostin 和 DMSO。术后，在第 3 天采集静脉移植物用于使用抗磷酸酪氨酸抗体（PY - 20）进行 Western 分析以评估酪氨酸激酶活性，并在第 28 天用于形态学或收缩功能研究。
与 DMSO 处理的静脉移植物相比，TKI 局部应用于静脉移植物使内膜增生减少了 49%（31±4 微米对 61±5 微米，P < 0.01）。与对照组相比，单独使用 DMSO 治疗使内膜增生减少了 28%（85±4 微米，P < 0.05）。DMSO 和 TKI 处理的静脉移植物中的收缩反应相当。Western 分析显示，与对照组相比，TKI 处理使酪氨酸磷酸化降低了 39 倍。
本研究表明，TKI 局部短期治疗可使内膜增生减少 49%，提示酪氨酸残基的磷酸化参与了导致静脉移植物内膜增生发展的信号通路。
