血栓素合成酶缺陷對於動脈內膜增生的影響及其相關機制

The effects of thromboxane A2 synthase deficiency on neointimal hyperplasia and the related mechanism

管奕奕(I-I Guang)

指導教授 ： 陳玉怜

國立臺灣大學/醫學院/解剖學研究所/碩士(2006年)

https://doi.org/10.6342/NTU.2006.10422

摘要

引發血管再狹窄的主要原因之一是由於血管受傷，使血管壁內皮損傷，平滑肌細胞直接暴露於流動的血液，刺激血小板的大量活化與聚集，釋放及分泌促發炎因子造成血管的發炎反應並且形成血栓，使得位在中層的平滑肌細胞增生和移行，造成內膜增生。而在血小板的活化過程中，血栓素扮演了重要的角色。本篇論文當中，利用血栓素合成酶缺陷小鼠，探討股動脈擴張手術對其血管再狹窄的影響以及當中的機制。研究顯示:在動物模式中，經過股動脈擴張手術之後，野生型小鼠 (C57BL/6) 的血管之新生內膜相當厚 (內膜/中膜之比率：2.6±0.4)，而血栓素合成酶缺陷小鼠的內膜增生情形相對的大幅度減少 (1.1±0.1)。以免疫組織染色法以及西方點墨法觀察，發現血栓素合成酶缺陷小鼠的新生內膜之COX-2與MMP-9表現相較於野生型小鼠也是減少的情形。在細胞模式中，將主動脈平滑肌細胞自野生型小鼠體內分離出來，以野生型和血栓素合成酶缺陷小鼠之活化的血小板刺激細胞，觀察其COX-2的表現。結果以野生型小鼠之活化的血小板刺激之下，平滑肌細胞的COX-2表現大量上升，而血栓素合成酶缺陷小鼠之活化的血小板刺激細胞之後，其COX-2表現相對減少。自上述實驗結果得知，血栓素合成酶缺陷的情形下，造成血栓素的缺乏，降低內膜增生和血管的發炎反應，表示抑制血栓素的形成能有效治療血管再狹窄。

關鍵字

內膜增生 ； 血小板 ； 平滑肌細胞 ； 血栓素 ； 環氧化酶基質金屬酶

並列摘要

Platelets activation and aggregation are important factors in restenosis. Thromboxane A2 (TXA2) plays a major role in homeostasis, thrombosis, vasoconstriction, and vascular cell proliferation. Thromboxane A2 synthase (TXAS) is the key enzyme in TXA2 biosynthesis. The previous study has demonstrated that TXAS deletion protects mice against arachidonate-induced shock and death. To investigate the effects of TXA2 on neointimal hyperplasia and cyclooxygenase-2 (COX-2, an inflammatory cytokine), we used TXAS–/– mice as an animal model. A wire injury of the right femoral artery was performed when the age of mice was 5 months. Right and left femoral arteries of wild type and TXAS–/– mice were harvested at the end of 4 weeks of the injury. The neointimal hyperplasia in right femoral artery was significantly inhibited in TXAS–/–mice. The area ratios of the neointima to the media in the right femoral artery of TXAS–/–mice (intima/media ratio: 1.1±0.1) were significantly less when compared to that of wild type (2.6±0.4). The intima of left femoral arteries in TXAS–/– mice and wild type showed very thin. Weaker COX-2 and MMP-9 expressions were seen in the neointimal area of TXAS–/–mice. The thickened intima was composed of smooth muscle cells mainly. In cell culture model, isolated aortic smooth muscle cells from wild type mice was treated with thrombin-activated platelets supernatant from wild type and TXAS–/–mice. These results showed that COX-2 expression of smooth muscle cells was highly induced under the treatment of activated platelets from wide type mice. In contrast, COX-2 expression was attenuated in smooth muscle cells under the treatment of activated platelets from TXAS-/- mice. Base on these studies, we conclude that TXA2 may offer some effects on post-angioplasty restenosis and the inhibitory effects on intimal response after wire injury might be attributed to the deficiency of TXA2

並列關鍵字

neointima hyperplasia ； platelet ； smooth muscle cell ； thromboxane A2 ； cyclooxygenase-2 ； matrix metalloprotease-9

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