本文選題：心肌纖維化 + 血管緊張素II�。� 參考：《山西醫(yī)科大學(xué)》2016年博士論文

【摘要】：研究背景:目前,各種心血管疾病如高血壓、缺血性心臟病或心臟瓣膜病等導(dǎo)致的心肌纖維化是40%-50%的心臟衰竭患者左室舒張功能不全的主要原因。心肌纖維化的主要病理特點(diǎn)是纖維狀膠原蛋白堆積,由血管周圍向心肌組織間隙呈彌漫性分布。大量的膠原蛋白堆積,且得不到及時(shí)的降解,使心肌順應(yīng)性減弱,心室充盈受阻,最終導(dǎo)致心臟衰竭。大量的基礎(chǔ)研究及臨床試驗(yàn)表明,通過激活腎素-血管緊張素系統(tǒng)(renin-angiotensin system)產(chǎn)生的血管緊張素II(Angiotension II,Ang II),是高血壓、心肌纖維化及心臟衰竭等發(fā)生的重要病理基礎(chǔ)。隨著對(duì)這一激素體液系統(tǒng)在心血管損傷方面的深入研究,以及針對(duì)Ang II在體內(nèi)含量變化所采取的相應(yīng)治療手段的進(jìn)展,人們對(duì)Ang II與各種心血管疾病的發(fā)生發(fā)展關(guān)系,有了深刻的理解和認(rèn)識(shí)。眾所周知,血管緊張素轉(zhuǎn)換酶抑制劑(Angiotensin converting enzyme inhibitor,ACEI)與血管緊張素受體拮抗劑(Angiotensin receptor blocker,ARB)為臨床治療各類心血管病的常規(guī)藥。通過ACEI減少Ang II的生成,以及利用ARB阻斷Ang II的作用,從而達(dá)到治療目的。但在實(shí)際臨床應(yīng)用中,這兩類藥物具有一定的副作用。ACEI可引起干咳,血管神經(jīng)性水腫,具有高腎素敏感性,且腎動(dòng)脈狹窄患者禁用;ARB可導(dǎo)致低血壓,而且存在患者藥物敏感性差異顯著等,這些問題均限制了ACEI、ARB在一些患者中的使用。因此,尋找其它的具有減輕Ang II損傷作用,進(jìn)而改善心血管患者預(yù)后的藥物,并澄清其作用機(jī)制,具有重要的臨床意義。姜黃素,是從植物姜黃的根莖中提取的黃色素,已被證實(shí)具有多種潛在的機(jī)體保護(hù)作用,如抗氧化,抗炎和抗纖維化等。因此,姜黃素受到人們極大的關(guān)注。本研究小組曾報(bào)道,在心梗引發(fā)心衰的大鼠模型中,姜黃素可以減小缺血后心臟梗死面積,進(jìn)而改善心臟功能。然而,姜黃素在心衰發(fā)生發(fā)展過程中是否通過抗纖維化發(fā)揮保護(hù)作用,且是否與調(diào)制血管緊張素轉(zhuǎn)換酶或血管緊張素II受體有關(guān)還不清楚。為此,本研究通過在大鼠缺血再灌注引起的心衰模型中,觀察姜黃素對(duì)心肌纖維化的作用及機(jī)制。研究結(jié)果發(fā)現(xiàn)姜黃素可通過抑制心肌纖維化,進(jìn)而改善心功能,且其發(fā)揮抗纖維化作用是通過雙重調(diào)節(jié)血管緊張素轉(zhuǎn)換酶與血管緊張素II受體實(shí)現(xiàn)的。為了進(jìn)一步證實(shí)姜黃素對(duì)Ang II所致心肌纖維化的保護(hù)效應(yīng)并研究其發(fā)揮保護(hù)作用的信號(hào)通路,我們利用微滲透泵人工直接輸注Ang II引起高血壓的大鼠模型。結(jié)果發(fā)現(xiàn)姜黃素的抗纖維化作用是通過下調(diào)AT1受體,上調(diào)AT2受體,進(jìn)一步抑制TGFβ1/Smad信號(hào)通路,以及增強(qiáng)ACE2表達(dá)實(shí)現(xiàn)的。本實(shí)驗(yàn)研究包括以下兩部分:第一部分姜黃素通過抑制血管緊張素轉(zhuǎn)化酶及拮抗血管緊張素ⅡAT1受體發(fā)揮抗心肌纖維化作用研究目的:觀察心梗后心肌纖維化時(shí)血管緊張素轉(zhuǎn)化酶、血管緊張素II受體的變化特點(diǎn),探討姜黃素在血管緊張素II所致纖維化中的保護(hù)作用及可能機(jī)制。研究假設(shè):已有的工作證實(shí),Ang II是心肌纖維化、心衰發(fā)生的重要病理性基礎(chǔ)。姜黃素具有抗纖維化作用。我們?cè)l(fā)現(xiàn),姜黃素減小心肌缺血后的梗死范圍,并能改善心衰患者的心功能。提示姜黃素減輕心梗后心肌纖維化可能與調(diào)節(jié)Ang II有關(guān)。這些結(jié)果將為我們進(jìn)一步澄清姜黃素的心臟保護(hù)效應(yīng),提供工作基礎(chǔ)。我們假設(shè),姜黃素抑制纖維化過程改善心功能的保護(hù)效應(yīng)是通過改變血管緊張素轉(zhuǎn)化酶及血管緊張素Ⅱ受體的表達(dá)而實(shí)現(xiàn)的。方法:體內(nèi)實(shí)驗(yàn)在缺血再灌注的大鼠模型進(jìn)行,胃管給予姜黃素(150 mg/kg/day)。分別在再灌注后7天和42天,超聲檢測(cè)心臟功能及室壁厚度;提取心肌組織,利用Masson’s trichrome染色檢測(cè)心肌纖維化;Western-blot進(jìn)行蛋白定量分析,包括ACE、AT1R、AT2R;免疫組化染色觀察各受體原位表達(dá)情況。體外實(shí)驗(yàn)在過氧化氫刺激下的H9c2細(xì)胞進(jìn)行,檢測(cè)AT1受體表達(dá)情況,細(xì)胞活性檢測(cè)采用MTT及PI染色。結(jié)果:超聲心動(dòng)圖結(jié)果表明,姜黃素組梗死前壁厚度明顯厚于對(duì)照組。給予姜黃素的大鼠左室短軸縮短率和射血分?jǐn)?shù)增加。Masson’s trichrome染色結(jié)果提示姜黃素不僅減少了纖維化心肌層的膠原沉積,也縮小了富含膠原的瘢痕范圍,使具有收縮功能的心肌細(xì)胞增多。與對(duì)照組相比,姜黃素能顯著降低ACE和AT1受體的蛋白表達(dá)水平,免疫組化染色顯示姜黃素減少心肌組織和冠脈中ACE和AT1受體表達(dá)。同時(shí),與對(duì)照組相比,姜黃素可顯著增加AT2受體的表達(dá)。在培養(yǎng)的心肌細(xì)胞,姜黃素抑制由氧化劑引起的AT1受體的表達(dá),并能增強(qiáng)細(xì)胞活性。結(jié)論:上述結(jié)果表明,再灌注過程中,口服姜黃素抑制ACE和AT1受體的表達(dá);同時(shí)增強(qiáng)AT2受體表達(dá)。姜黃素的保護(hù)效應(yīng)由AT1受體與AT2受體的比值減小可證明。與此發(fā)現(xiàn)相一致,缺血/再灌注的心室壁上膠原沉積、纖維化的組織減少,這也進(jìn)一步證明姜黃素可以增加心室壁厚度。此外,左室短軸縮短率和射血分?jǐn)?shù)增加,表明心臟收縮功能得到改善。體外實(shí)驗(yàn)表明,以氯沙坦處理的細(xì)胞作為對(duì)照,姜黃素抑制H2O2誘導(dǎo)的H9c2細(xì)胞AT1受體的表達(dá),提高細(xì)胞的存活率,提示姜黃素能夠通過調(diào)節(jié)AT1受體保護(hù)細(xì)胞免受氧化劑誘導(dǎo)的細(xì)胞損傷。第二部分姜黃素通過血管緊張素II受體/TGFβ1/Smad通路及血管緊張素轉(zhuǎn)化酶2抑制心肌纖維化研究目的:探討姜黃素抗心肌纖維化的作用機(jī)理。研究假設(shè):實(shí)驗(yàn)研究的第一部分提示,Ang II具有致心肌纖維化作用,這些變化可被姜黃素所逆轉(zhuǎn)。我們已發(fā)表的研究發(fā)現(xiàn),姜黃素通過平衡膠原的合成與降解使心肌梗死后的心功能得到改善。在心肌纖維化的發(fā)生發(fā)展中,纖維化轉(zhuǎn)化生長(zhǎng)因子-β1(Transforming growth factor beta-1,TGFβ1)和Smads調(diào)定下游膠原為主要的信號(hào)轉(zhuǎn)導(dǎo)通路。但姜黃素逆轉(zhuǎn)組織纖維化是否有這一通路的參與目前仍不明確。另外,Ang II可激活其AT1和AT2兩種受體;AT1具有縮血管,促進(jìn)組織纖維化的作用;而活化AT2受體產(chǎn)生相反的保護(hù)效應(yīng)。血管緊張素轉(zhuǎn)化酶2(Angiotensin-converting enzyme 2,ACE2)與ACE同源,將Ang II轉(zhuǎn)化成Ang(1-7)并發(fā)揮心肌保護(hù)效應(yīng)。因此,我們假設(shè),姜黃素具有調(diào)定AT1、AT2受體和ACE2的作用,進(jìn)而抑制Ang II導(dǎo)致的心肌纖維化。方法:實(shí)驗(yàn)在背部皮下包埋植入微型滲透泵直接輸注Ang II(500 ng/kg/min)的大鼠模型進(jìn)行,胃管給予姜黃素(150 mg/kg/day)。無(wú)創(chuàng)監(jiān)測(cè)輸注Ang II后0,7,14,28天的血壓變化。分別在2周和4周后,提取心肌組織,利用Masson染色檢測(cè)心肌纖維化;Western-blot測(cè)定AT1、AT2、ACE2、TGFβ1、p-Smad2,3、I型膠原蛋白含量;免疫組化染色檢測(cè)各受體和通道蛋白原位表達(dá)、巨噬細(xì)胞聚集及成纖維細(xì)胞增生情況。結(jié)果:Ang II輸注7天后,與假手術(shù)(Sham)組相比,對(duì)照組(Control)血壓明顯升高,并且隨著輸注時(shí)間的延長(zhǎng)逐漸升高,到21天時(shí)血壓值達(dá)到高峰,且一直保持較高水平,直至實(shí)驗(yàn)結(jié)束。Ang II輸注2周后,心肌纖維化開始發(fā)生變化,但不具有統(tǒng)計(jì)學(xué)差別;而在4周后,心肌纖維化出現(xiàn)了明顯的組織病理學(xué)改變,表現(xiàn)為:心肌組織小動(dòng)脈、小靜脈以及毛細(xì)血管管周圍纖維組織明顯增生,結(jié)構(gòu)紊亂;心肌組織中纖維化明顯,呈條索或片狀散在分布于心肌層。CD68標(biāo)記的巨噬細(xì)胞和由a-平滑肌肌動(dòng)蛋白(a-smooth muscle actin,a-SMA)標(biāo)記的肌成纖維細(xì)胞,在組織中聚集明顯增多,心肌組織Ⅰ型膠原含量增加。姜黃素對(duì)輸注Ang II 2周時(shí)的組織變化無(wú)顯著影響;但在4周時(shí),與對(duì)照組相比,姜黃素顯著減小了心肌纖維化的范圍;巨噬細(xì)胞和活化的成纖維細(xì)胞聚集減少,I型膠原含量減少。與Sham組相比,對(duì)照組在AngⅡ慢性輸注2周,AT1受體表達(dá)稍有增加,無(wú)統(tǒng)計(jì)學(xué)差別;AT2受體表達(dá)減少;但對(duì)照組在輸注4周后,AT1受體表達(dá)明顯增加,AT2受體表達(dá)減少;免疫組化染色檢測(cè)也發(fā)現(xiàn),心肌血管壁周圍和心肌組織中的AT1受體表達(dá)增強(qiáng)和AT2受體表達(dá)減弱。與這些變化相一致,TGFβ1蛋白和p-Smad2、p-Smad3表達(dá)增加。此外,ACE2表達(dá)減少。姜黃素干預(yù)4周后,上述變化明顯得到改善。表現(xiàn)為:AT1受體表達(dá)明顯減少,AT2受體表達(dá)增加,免疫組化染色檢測(cè)也證實(shí),血管壁周圍和心肌組織中的AT1受體減弱,AT2受體表達(dá)增強(qiáng)。與姜黃素抑制膠原蛋白減少纖維化作用一致,TGFβ1、p-Smad2、p-Smad3表達(dá)減少。此外,ACE2表達(dá)增加;免疫組化染色顯示心肌組織中ACE2表達(dá)增強(qiáng)。結(jié)論:上述結(jié)果表明,Ang II具有顯著的致心肌組織纖維化作用。Ang II可引起組織間隙巨噬細(xì)胞和成纖維細(xì)胞聚集增加,并伴有Ⅰ型膠原增生。這些現(xiàn)象在Ang II輸注4周時(shí)最為明顯。實(shí)驗(yàn)發(fā)現(xiàn),姜黃素具有明顯的抗心肌纖維化作用。探究其作用機(jī)制,參與Ang II致心肌纖維化的信號(hào)傳導(dǎo)通路為血管緊張素II AT1/TGFβ1/Smad。Ang II通過改變AT1/AT2相對(duì)表達(dá)含量,進(jìn)而使TGFβ1受體表達(dá)增加,并持續(xù)激活下游Smad通路,引起心肌細(xì)胞纖維化。姜黃素一方面平衡此通路中AT1、AT2的表達(dá)水平,另一方面還上調(diào)ACE2的表達(dá),使大量Ang II降解為Ang1-7。同以往研究結(jié)果一致,姜黃素具有心血管保護(hù)作用。在本研究中,姜黃素可抑制Ang II直接刺激后的心臟損傷,為進(jìn)一步研究姜黃素對(duì)心血管系統(tǒng)的保護(hù)作用提供直接、有力的證據(jù)。本研究展望我們的研究首次證明姜黃素抗纖維化作用與拮抗血管緊張素II受體和血管緊張素轉(zhuǎn)化酶有關(guān),與此同時(shí),我們觀察到姜黃素還可以降低血管緊張素II引起的高血壓,這些結(jié)果為進(jìn)一步明確姜黃素的心血管保護(hù)作用提供了直接的實(shí)驗(yàn)依據(jù)。姜黃素,作為一種植物提取物,在印度被人們作為調(diào)料每日食用,其藥力動(dòng)力學(xué)、安全性及療效已被臨床前研究及臨床試驗(yàn)所證實(shí)。本實(shí)驗(yàn)結(jié)果還提示,藥食兩用的姜黃素有望與其它臨床常規(guī)使用藥物,如ACE抑制劑,AT1受體阻斷劑或β受體阻斷劑等聯(lián)合用藥,以減輕患者對(duì)其它藥物的副作用,并為對(duì)此類藥物禁忌的患者帶來(lái)福音,進(jìn)而提高藥物在治療高血壓,缺血性心臟病和心衰等心血管疾病的療效,并改善患者的預(yù)后。
[Abstract]:Background: myocardial fibrosis caused by various cardiovascular diseases such as hypertension, ischemic heart disease or heart valvular disease is the main cause of left ventricular diastolic dysfunction in patients with 40%-50% heart failure. The main pathological feature of myocardial fibrosis is fibrous collagen accumulation, from the perivascular to the interventricular space. Diffuse distribution. A large amount of collagen accumulation, and not timely degradation, makes myocardial compliance weakens, ventricular filling is blocked, and eventually leads to heart failure. A large number of basic research and clinical trials have shown that the angiotensin II (Angiotension II, Ang II) produced by the renin angiotensin system (renin-angiotensin system) is activated. It is an important pathological basis for hypertension, myocardial fibrosis and heart failure. With the deep research on the cardiovascular damage of this hormone body fluid system and the progress of the corresponding treatment for the changes in the content of Ang II in the body, people have a profound relationship with the development of Ang II and the development of various kinds of cardiovascular diseases. Understanding and understanding. It is known that the angiotensin converting enzyme inhibitor (Angiotensin converting enzyme inhibitor, ACEI) and angiotensin receptor antagonist (Angiotensin receptor blocker, ARB) are the conventional drugs for the clinical treatment of all kinds of cardiovascular diseases. In actual clinical applications, but in practical clinical applications, these two kinds of drugs have a certain side effect.ACEI can cause dry cough, angioedema, high renin sensitivity, and renal artery stenosis patients are prohibited; ARB can cause hypotension, and there is a difference in drug sensitivity in patients. These problems are all limited to ACEI, ARB in some It has important clinical significance to find other drugs that can reduce the Ang II damage and improve the prognosis of cardiovascular patients and clarify its mechanism. Curcumin, a yellow pigment extracted from the rhizomes of the plant Curcuma, has been proved to have a variety of potential protective effects, such as antioxidant and anti-inflammatory. Therefore, curcumin has been greatly concerned. This research team has reported that curcumin can reduce the infarct size and improve cardiac function in rats with heart failure caused by myocardial infarction. However, curcumin plays a protective role in the development of heart failure through anti fibrosis, and it is a protective effect of curcumin on the development of heart failure. It is not clear that the modulation of angiotensin converting enzyme or angiotensin II receptor is not clear. To this end, this study observed the effect and mechanism of curcumin on myocardial fibrosis in the model of heart failure induced by ischemia-reperfusion in rats. The results showed that curcumin could inhibit cardiac fibrosis and then improve cardiac function, and it exerts resistance to the heart. The effect of fibrosis is realized by double regulation of angiotensin converting enzyme and angiotensin II receptor. In order to further confirm the protective effect of curcumin on Ang II induced myocardial fibrosis and to study the signaling pathway of its protective effect, the rat model of hypertension induced by Ang II induced by artificial infusion of microosmotic pump was used. The anti fibrosis effect of curcumin was found by down regulating the AT1 receptor, up regulating the AT2 receptor, further inhibiting the TGF beta 1/Smad signaling pathway and enhancing the expression of ACE2. This experimental study includes the following two parts: Part 1: Curcumin exerts anti myocardial fiber by inhibiting angiotensin converting enzyme and antagonizing angiotensin II AT1 receptor Objective: To observe the changes of angiotensin converting enzyme (angiotensin converting enzyme) and angiotensin II receptor (angiotensin) receptor (angiotensin) receptor (angiotensin) in myocardial fibrosis after myocardial infarction (MI) and explore the protective effect and mechanism of curcumin in angiotensin II induced fibrosis. The research hypothesis: Ang II is an important pathological basis for myocardial fibrosis and heart failure. Curcumin has an anti fibrosis effect. We have found that curcumin reduces the infarct range after myocardial ischemia and improves cardiac function in patients with heart failure. It is suggested that curcumin may be related to the regulation of Ang II after myocardial infarction. These results will provide a basis for further clarification of the protective effect of curcumin on the heart. We hypothesized that the protective effect of curcumin on the improvement of cardiac function by inhibiting the process of fibrosis is achieved by changing the expression of angiotensin converting enzyme and angiotensin II receptor. Methods: in the rat model of ischemia reperfusion in vivo, the gastric tube was given curcumin (150 mg/kg/day), 7 days and 42 days after reperfusion, respectively. The cardiac function and wall thickness were detected; myocardial tissue was extracted and Masson 's trichrome staining was used to detect myocardial fibrosis; Western-blot was used for quantitative analysis of protein, including ACE, AT1R, AT2R; immunohistochemical staining was used to observe the expression of each receptor in situ. In vitro experiments were carried out in H9c2 cells stimulated by hydrogen peroxide to detect the expression of AT1 receptor. MTT and PI staining were used to detect the cell activity. Results: the results of echocardiography showed that the thickness of the anterior wall of the curcumin group was significantly thicker than that of the control group. The short axis shortening rate and the ejection fraction of curcumin increased by.Masson 's trichrome staining results suggested that curcumin not only reduced the collagen deposition of the fibrotic myocardium, but also reduced the collagen deposition. Cicatricial areas rich in collagen made the myocardial cells with contractile function increased. Compared with the control group, curcumin could significantly reduce the protein expression level of ACE and AT1 receptors. The immunohistochemical staining showed that curcumin reduced the expression of ACE and AT1 receptors in the myocardium and coronary artery. Meanwhile, curcumin could significantly increase the AT2 receptor compared with the control group. In cultured cardiac myocytes, curcumin inhibited the expression of AT1 receptor induced by oxidant and enhanced cell activity. Conclusion: the above results show that the oral curcumin inhibits the expression of ACE and AT1 receptors and increases the expression of AT2 receptor in the process of reperfusion. The protective effect of curcumin decreases from the ratio of AT1 receptor to AT2 receptor. It was proved that, in accordance with this discovery, the collagen deposition on the ventricular wall of ischemia / reperfusion and the fibrosis tissue decreased, which further demonstrated that curcumin could increase the thickness of the ventricular wall. In addition, the short axis shortening rate and the ejection fraction of the left ventricle increased, indicating that the systolic function of the heart was improved. In vitro experiments showed that the cells treated with losartan were used in vitro. Curcumin inhibits the expression of AT1 receptor in H9c2 cells induced by H2O2 and improves cell survival, suggesting that curcumin can protect cells from AT1 receptors to protect cells from oxidative induced cell damage. Second part curcumin can inhibit myocardial fibrosis through angiotensin II receptor /TGF beta 1/Smad pathway and angiotensin converting enzyme 2 Objective: To explore the mechanism of curcumin against myocardial fibrosis. Research hypothesis: the first part of the experimental study suggests that Ang II can induce myocardial fibrosis, and these changes can be reversed by curcumin. Our published studies have found that the cardiac function of curcumin can be modified by the synthesis and degradation of the balance collagen. Good. In the development of myocardial fibrosis, fibrotic transforming growth factor - beta 1 (Transforming growth factor beta-1, TGF beta 1) and Smads regulating downstream collagen are the main signal transduction pathways. However, the involvement of curcumin in tissue fibrosis is still unclear. In addition, Ang II activates two kinds of receptors of AT1 and AT2. AT1 has a vasoconstrictor that promotes tissue fibrosis, and activates the AT2 receptor to produce an opposite protective effect. Angiotensin converting enzyme 2 (Angiotensin-converting enzyme 2, ACE2) is homologous to ACE, transforming Ang II into Ang (1-7) and exerting myocardial protective effect. Therefore, we hypothesize that curcumin has the role of regulating AT1, AT2 receptors and ACE2. And then inhibit the myocardial fibrosis caused by Ang II. Methods: the rat model was implanted subcutaneously into the back subcutaneously implanted into the rat model of Ang II (500 ng/kg/min), and the gastric tube was given curcumin (150 mg/kg/day). The blood pressure changed after Ang II without invasive monitoring. The myocardial tissue was extracted after 2 weeks and 4 weeks, and Masso was extracted with Masso respectively. N staining was used to detect myocardial fibrosis; Western-blot was used to determine the content of AT1, AT2, ACE2, TGF beta 1, p-Smad2,3, I type collagen; immunohistochemical staining was used to detect the expression of each receptor and channel protein in situ, macrophage aggregation and fibroblast proliferation. Results: Ang II infusion 7 days later, compared with the sham group (Sham), the control group (Control) blood pressure was obviously increased High, and as the time of infusion increased gradually, the blood pressure reached a peak at 21 days and kept a high level until the end of the.Ang II infusion. After 2 weeks, the myocardial fibrosis began to change, but no statistical difference was found; and after 4 weeks, the myocardial fibrosis appeared obvious histopathological changes, manifested as: myocardium Tissue arterioles, small veins and capillary tubes were obviously proliferated and disorganized around the capillary tube, and the fibrosis was obvious in the myocardium. The myofibroblast and myofibroblast marked by.CD68 and a- muscle actin (a-Smooth muscle actin, a-SMA) were marked in the myocardium. In addition, the content of type I collagen in myocardial tissue increased. Curcumin had no significant effect on the tissue changes at the time of infusion of Ang II at the 2 week, but at the 4 week, curcumin significantly reduced the range of myocardial fibrosis, the accumulation of macrophages and activated fibroblasts decreased, and the content of type I collagen decreased. Compared with the Sham group, the control group was Ang II. After 2 weeks of chronic infusion, the expression of AT1 receptor was slightly increased, and the expression of AT2 receptor decreased, but in the control group, the expression of AT1 receptor was significantly increased and the expression of AT2 receptor decreased after 4 weeks of infusion. Immunohistochemical staining also found that the expression of AT1 receptor in the surrounding and myocardial tissue of the myocardium was enhanced and the expression of AT2 receptor weakened. In addition, the expression of TGF beta 1 protein and p-Smad2 and p-Smad3 was increased. In addition, the expression of ACE2 decreased. After 4 weeks of curcumin intervention, the above changes were obviously improved. The expression of AT1 receptor expression was significantly reduced, the expression of AT2 receptor was increased, and immunohistochemical staining showed that the AT1 receptor in the surrounding and myocardial tissues of the vascular wall weakened, and the expression of AT2 receptor increased. In addition, the expression of TGF beta 1, p-Smad2 and p-Smad3 decreased. In addition, the expression of ACE2 was increased, and the expression of ACE2 in the myocardium was enhanced by immunohistochemical staining. Conclusion: These results suggest that Ang II has a significant role in myocardial fibrosis and.Ang II can cause interstitial macrophages and interstitial macrophages. The aggregation of fibroblasts increased and was accompanied by type I collagen proliferation. These phenomena were most obvious at the 4 week of Ang II infusion. It was found that curcumin had obvious anti fibrosis effect. The mechanism of action was explored and the signal transduction pathway involved in Ang II induced myocardial fibrosis was angiotensin II AT1/TGF beta 1/Smad.Ang II by changing AT1/AT 2 relative expression levels, and then increase the expression of TGF beta 1 receptor, and continue to activate the downstream Smad pathway to cause myocardial fibrosis. Curcumin balanced the expression of AT1, AT2 in this pathway, on the other hand, up regulation of ACE2 expression, so that a large number of Ang II degrades to Ang1-7., and curcumin has cardiovascular protection. In this study, curcumin can inhibit the heart damage of direct stimulation of Ang II and provide direct and powerful evidence for the protective effect of curcumin on the cardiovascular system. This study looks forward to our study for the first time to demonstrate the anti fibrosis effect of curcumin and the antagonism of the blood angiotensin II receptor and angiotensin converting enzyme. At the same time, we observed that curcumin can also reduce the hypertension caused by angiotensin II. These results provide a direct experimental basis for further clarification of the protective effect of curcumin on cardiovascular protection. Curcumin, used as a plant extract, is eaten daily in India as a seasoning, and its pharmacological dynamics, safety and The results have been confirmed by preclinical studies and clinical trials. The results also suggest that curcumin is a promising alternative to other clinical practice.
【學(xué)位授予單位】：山西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R542.23

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