13-methyltetradecanoic acid (13-MTD)在大鼠頸動脈模式中對氣球擴張術後內膜新生之抑制機轉; The inhibitory mechanisms of 13-methyltetradecanoic acid (13-MTD) on balloon injury-induced neointima formation in the rat carotid artery model

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题名:	13-methyltetradecanoic acid (13-MTD)在大鼠頸動脈模式中對氣球擴張術後內膜新生之抑制機轉;The inhibitory mechanisms of 13-methyltetradecanoic acid (13-MTD) on balloon injury-induced neointima formation in the rat carotid artery model
作者:	簡義忠;Yi-Chung Chien
贡献者:	中國醫藥大學醫學研究所
关键词:	平滑肌細胞;再阻塞;脂肪酸;粥狀動脈硬化;13-MTD;smooth muscle cell;restenosis;PTCA
日期:	2004
上传时间:	2010-01-20 16:53:42 (UTC+8)
摘要:	氣球擴張術經常應用於治療冠狀動脈粥狀硬化疾病引起之血管阻塞。然而，大約有30 %~50 %左右曾經接受過氣球擴張術治療的病患，於半年內會有血管再阻塞(restenosis)的不良情況發生。所以，血管再阻塞的情形即成為氣球擴張術這項技術應用上的最大缺點。一般認為，血管結構在遭受氣球擴張術破壞後，會促使血管內平滑肌細胞的增生和遷移作用，進而產生新生內膜(neointima)成為血管再阻塞的主要原因。所以，本篇研究的目的在利用13-methyltetradecanoic acid 應用在大鼠的頸動脈動物模式中探討其是否具有治療氣球擴張術引起的內膜增生並探討在體外模式中其可能之作用機轉。在體外的(in vitro)細胞培養方面，分別給予A10 細胞株不同濃度的13-methyltetradecanoic acid (各為0.021、0.041、0.083、0.165和0.331 μM)處理後，抽取蛋白質進行西方墨點法分析。研究的結果顯示許多與調節細胞週期相關的蛋白質(例如：24 hours PCNA、24 hours Raf、24 hours Erk 2、30 minutes and 24 hours p-Erk 2)表現量與對照組(control)相比較皆有下降的趨勢，且藥物的抑制作用呈現劑量依附特性。此外，應用MTT分析細胞增生的結果顯示，A10 細胞經由13-methyltetradecanoic acid處理後24小時與對照組比較具有明顯抑制細胞增生的情形(p < 0.01)。在動物體內(in vivo)實驗方面，實驗動物在接受頸動脈氣球破壞之後，每天以灌食的方式給予不同濃度(109和163 mg/kg)的13-methyltetradecanoic acid持續14天。組織切片結果顯示濃度109和163 mg/kg的13-methyltetradecanoic acid 相較於假手術組(sham controls)，可以明顯抑制氣球破壞後的血管再阻塞情形。綜合本篇研究的結果可發現，13-methyltetradecanoic acid對於氣球破壞後血管內膜新生的情形，有很明顯的抑制作用，而在體外的實驗中，也可以發現13-methyltetradecanoic acid能夠抑制Mitogen activated protein kinase pathway早期的訊息傳導，因此13-methyltetradecanoic acid可能可用來當做治療氣球擴張術之後新生內膜所產生的再阻塞現象。; Percutaneous coronary angioplasty is usually indicated for atherosclerosis-induced coronary obstruction. Unfortunately, there are approximately 30% to 50% of patients receiving PTCA suffered from restenosis within 6 months. Thus, the present study was to examine if 13-methyltetradecanoic acid (13-MTD) could inhibit the neointima proliferation due to balloon injury-induced restenosis .We used the smooth muscle cell line (A10) and Sprague-Dawley rats with various dosage of 13-MTD (0.021、0.041、0.083、0.165和0.331 μM) for MTT test , DNA laddering , Western blot , and animals morphology assay . In the in vitro study, total protein extracted from A10 cells treated with0.041、0.083、0.165和0.331 μM of 13-MTD was subjected to western blot analysis. Results showed that PCNA、Raf、p-ERK2 and ERK2 are in a dose-dependent manner as compared to the positive controls.In addition, MTT test demonstrated that 13-MTD significantly reduced proliferation of A10 cells as compared to the controls (p <0.01).Our in vivo results showed that the balloon injury-induced restenosis can be significantly inhibited by 109和163 mg/kg of 13-MTD as compared to the sham controls. The findings of the present study suggest that 13-MTD can be a potential candidate as the pharmacological approach to prevent PTCA-induced restenosis.
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