本文選題：腹主動(dòng)脈瘤 + 葛根素��； 參考：《南方醫(yī)科大學(xué)》2017年博士論文

【摘要】：背景:腹主動(dòng)脈瘤(AAA Abdominal Aortic Aneurysm)是指腹主動(dòng)脈發(fā)生局限性或彌漫性瘤樣膨大,一旦發(fā)生瘤體破裂,病死率高達(dá)78-94%。目前,對(duì)于直徑5.5cm、瘤體擴(kuò)張緩慢、近期破裂的風(fēng)險(xiǎn)很低的無(wú)癥狀小腹主動(dòng)脈瘤,尚無(wú)明確的干預(yù)措施,隨著患者年齡的增長(zhǎng),對(duì)于手術(shù)的耐受力逐漸下降,而瘤體的增長(zhǎng)和擴(kuò)張是不可逆的,必然導(dǎo)致老年后手術(shù)治療風(fēng)險(xiǎn)增大。對(duì)于此類(lèi)患者,目前臨床此類(lèi)藥物作用有限。因此,開(kāi)發(fā)針對(duì)腹主動(dòng)脈瘤發(fā)病機(jī)制的藥物對(duì)疾病的預(yù)防和治療具有重大意義。血管緊張素Ⅱ(angiotensinⅡ,AngⅡ)在腹主動(dòng)脈瘤的發(fā)生發(fā)展過(guò)程中起到重要作用。主要是通過(guò)激活下游信號(hào)通路,誘發(fā)氧自由基產(chǎn)生、平滑肌細(xì)胞凋亡、炎性因子表達(dá)和基質(zhì)金屬蛋白酶合成,從而加重腹主動(dòng)脈壁的炎癥反應(yīng),加速?gòu)椓w維、膠原蛋白降解和動(dòng)脈中膜的壞死,動(dòng)脈壁重塑,致使瘤體逐漸擴(kuò)張。葛根素是一種高效氧自由基清除劑,臨床上廣泛用來(lái)防止血栓栓塞性疾病。目前報(bào)道葛根素具有抗氧自由基損傷、細(xì)胞保護(hù)、抑制血管內(nèi)皮細(xì)胞組織因子的表達(dá)等多種作用。但其對(duì)于腹主動(dòng)脈瘤的作用尚未見(jiàn)研究,。本研究希望通過(guò)研究葛根素對(duì)于腹主動(dòng)脈瘤的作用及相關(guān)分子生物學(xué)機(jī)制,為腹主動(dòng)脈瘤的預(yù)防和治療提供啟發(fā)。目的:建立AngⅡ誘導(dǎo)的Apoe基因敲除小鼠腎下腹主動(dòng)脈瘤模型,就葛根素對(duì)腹主動(dòng)脈瘤生長(zhǎng)的影響從成瘤率、分子生物學(xué)等方面進(jìn)行觀察,研究葛根素對(duì)小鼠腹主動(dòng)脈的擴(kuò)張是否有抑制作用,在此基礎(chǔ)上進(jìn)一步闡釋的發(fā)病機(jī)制,為的臨床藥物治療提供參考。同時(shí)通過(guò)葛根素對(duì)EOMA細(xì)胞的增殖和凋亡作用,研究其對(duì)于新生炎癥血管生成的影響。方法:利用AngⅡ誘導(dǎo)在ApoE基因敲除小鼠上模擬人腹主動(dòng)脈瘤形成。并采用葛根素灌喂小鼠后與對(duì)照組比較腹主動(dòng)脈瘤成瘤發(fā)生率,NADPH氧化酶活性,MMP2激活情況,ROS生成情況,AP-1和p-Jun蛋白的表達(dá)情況。同時(shí)研究葛根素對(duì)EOMA細(xì)胞的增殖和凋亡作用,檢測(cè)EOMA細(xì)胞中caspase-9/3酶活性。結(jié)果:結(jié)果顯示,AngⅡ模型組腹主動(dòng)脈瘤的發(fā)生率為80%,而200mg/kg和100mg/kg葛根素治療組分別降至50%,30%;葛根素治療組中NADPH氧化酶活性,MMPs表達(dá),ROS產(chǎn)物,AP-1蛋白及p-Jun蛋白的表達(dá)相比于AngⅡ模型組顯著降低,同時(shí),葛根素顯著抑制EOMA細(xì)胞的增殖并誘導(dǎo)其凋亡,并顯著增加EOMA細(xì)胞內(nèi)caspase-9/3酶活性,提示其可促進(jìn)內(nèi)皮細(xì)胞凋亡,抑制新生血管生成。結(jié)論:葛根素可以顯著抑制AngⅡ誘導(dǎo)的腹主動(dòng)脈瘤形成。其可能的機(jī)制包括抑制ROS產(chǎn)物、降低基質(zhì)金屬蛋白酶的表達(dá)水平和活性,降低主動(dòng)脈瘤內(nèi)AP-1蛋白的表達(dá),同降低p-Jun蛋白表達(dá),抑制新生血管內(nèi)皮細(xì)胞增殖,促進(jìn)內(nèi)皮細(xì)胞凋亡,抑制細(xì)胞內(nèi)caspase-9/3酶活性。但其具體機(jī)制還需進(jìn)一步的研究。
[Abstract]:Background: AAA Abdominal Aortic neurysmis (AAA Abdominal Aortic Aneurysm) refers to localized or diffuse aneurysm like enlargement of the abdominal aorta. Once the tumor ruptures, the mortality rate is as high as 78-9445. At present, there is no clear intervention for asymptomatic abdominal aortic aneurysms with a diameter of 5.5 cm, a slow expansion of the tumor and a very low risk of rupture in the near future. As the patient grows older, his tolerance to surgery gradually decreases. The growth and expansion of the tumor is irreversible and will inevitably lead to increased risk of surgical treatment in old age. For such patients, the current clinical use of such drugs is limited. Therefore, the development of drugs for the pathogenesis of abdominal aortic aneurysm is of great significance for the prevention and treatment of the disease. Angiotensin 鈪，

本文編號(hào)：1845978