本文選題：高血壓 + 心臟纖維化��； 參考：《天津醫(yī)科大學(xué)》2017年博士論文

【摘要】：研究背景心臟纖維化可發(fā)生于各種心臟疾患,如高血壓、缺血性心臟病和心臟瓣膜病。當(dāng)前我國流行病學(xué)調(diào)查數(shù)據(jù)顯示,近年來15歲以上人群高血壓患病率已高達(dá)24%,累計高血壓患病人數(shù)達(dá)2.66億,每年新增高血壓病例約1000萬。由于人群中高血壓的治療率(24.7%)與控制率(6.1%)較低,高血壓已經(jīng)逐漸成為心臟纖維化的主要病因。高血壓導(dǎo)致的心臟纖維化表現(xiàn)為心臟組織中膠原合成與降解紊亂(包括原有膠原纖維網(wǎng)的降解和膠原纖維過度合成)、心肌細(xì)胞間隙膠原纖維異常沉積、心室壁順應(yīng)性下降和心臟肥厚,早期造成心臟舒張功能不全,逐漸造成收縮功能不全,最終導(dǎo)致心力衰竭。血管緊張素Ⅱ(AngiotensinⅡ,AngⅡ)在高血壓心臟纖維化的病理生理過程中發(fā)揮著重要作用,AngⅡ通過與AngⅡⅠ型受體(TypeⅠangiotensinⅡreceptor,AT_1R)結(jié)合使血管平滑肌收縮、激活炎癥細(xì)胞誘導(dǎo)機(jī)體炎癥反應(yīng),并刺激成纖維細(xì)胞過度表達(dá)膠原蛋白致組織間隙膠原纖維沉積造成心臟纖維化。目前針對AngⅡ誘發(fā)高血壓心臟纖維化的防治藥物主要包括血管緊張素轉(zhuǎn)換酶抑制劑(Angiotensin converting enzymeinhibitor,ACEI)和AT_1R拮抗劑(AngiotensinⅡreceptor blocker,ARB)兩大類藥物,目的在于減少AngⅡ的生成和抑制AT_1R激活。胰高血糖素樣肽-1(Glucagon-like peptide 1,GLP-1)是小腸內(nèi)分泌L細(xì)胞分泌的腸促胰島素激素,在維持人體餐后血糖穩(wěn)定方面發(fā)揮重要作用,但內(nèi)源性GLP-1分泌后迅速被體內(nèi)的二肽基肽酶-4(Dipeptidyl peptidase-4,DDP-4)降解,在人體內(nèi)的半衰期僅為1-2分鐘。因此為了延長其半衰期,人們發(fā)現(xiàn)了目前應(yīng)用于臨床2型糖尿病治療的GLP-1受體激動劑:艾塞那肽和利拉魯肽。臨床實踐發(fā)現(xiàn),GLP-1受體激動劑除了在糖尿病治療方面發(fā)揮控制血糖、改善胰島素抵抗等作用外,還在改善人體脂代謝、調(diào)節(jié)血管內(nèi)皮功能、預(yù)防動脈硬化和心臟保護(hù)方面發(fā)揮重要作用,提示這類藥物可為2型糖尿病患者帶來血糖控制與心血管保護(hù)的雙重獲益。動物實驗表明,GLP-1受體激動劑可縮小心肌梗死面積、減輕心肌缺血再灌注損傷、改善心臟功能,同時還能改善心肌梗死后心臟纖維化程度。在AngⅡ誘導(dǎo)的高血壓心臟纖維化模型中,GLP-1受體激動劑也可抑制血壓升高、抑制心臟肥厚并能改善心臟纖維化。此外,GLP-1受體激動劑抑制心臟纖維化的作用也在合并心力衰竭、心肌梗死或高血壓的2型糖尿病患者中得到證實。利拉魯肽與艾塞那肽肽鏈結(jié)構(gòu)不同,目前尚缺乏研究對比該兩種GLP-1受體激動劑對高血壓心臟纖維化的影響是否存在不同;且GLP-1受體激動劑對參與心臟纖維化進(jìn)程中不同細(xì)胞(心肌細(xì)胞、成纖維細(xì)胞、巨噬細(xì)胞)的作用也罕見報道。另外,對于GLP-1受體激動劑是否可直接作用于心肌成纖維細(xì)胞進(jìn)而參與心臟纖維化進(jìn)程,目前學(xué)界也存在爭議。因此本研究將分別利用利拉魯肽和艾塞那肽干預(yù)AngⅡ誘導(dǎo)的高血壓心臟纖維化體外培養(yǎng)細(xì)胞和小鼠模型以就上述3個問題進(jìn)行探討。研究目的1.觀察比較利拉魯肽和艾塞那肽對AngⅡ誘導(dǎo)的高血壓心臟纖維化小鼠心功能和心臟纖維化的作用;2.觀察利拉魯肽和艾塞那肽對于體外培養(yǎng)的心肌細(xì)胞、巨噬細(xì)胞和成纖維細(xì)胞在AngⅡ刺激下的作用;3.通過細(xì)胞共培養(yǎng)的方法,觀察在細(xì)胞水平GLP-1受體激動劑對心臟纖維化過程的作用方式。研究方法1.動物模型建立及藥物干預(yù)40只健康雄性C57BL/6J小鼠(體重21-26g)適應(yīng)性飼養(yǎng)1周后隨機(jī)分為4組。根據(jù)分組情況于小鼠背部植入膠囊滲透壓泵:對照組植入滲透壓泵中含有生理鹽水,AngⅡ組、AngⅡ+利拉魯肽組、AngⅡ+艾塞那肽組植入含有AngⅡ的膠囊滲透壓泵以1.44mg/kg/d的速度恒速釋放AngⅡ28d;AngⅡ+利拉魯肽組和AngⅡ+艾塞那肽組分別于術(shù)前72h給予利拉魯肽0.4 mg/kg/d和艾塞那肽0.1mg/kg/d腹腔注射直至實驗結(jié)束。實驗結(jié)束后對小鼠進(jìn)行稱重、血糖試紙檢測空腹血糖,然后安樂死處死小鼠,留取心臟組織標(biāo)本。2.超聲心動圖評價小鼠心臟結(jié)構(gòu)與功能實驗?zāi)⿲λ行∈筮M(jìn)行超聲心動圖檢查,利用二維超聲和M型超聲成像技術(shù)測定左心室收縮末期內(nèi)徑(Left ventricular internal dimension in systole,LVIDs)、左心室舒張末期內(nèi)徑(Left ventricular internal dimension in diastole,LVIDd)、室間隔收縮末期厚度(Interventricular septal width in systole,IVSs)、室間隔舒張末期厚度(Interventricular septal width in diastole,IVSd)、左室后壁收縮末期厚度(Left ventricular posterior wall width in systole,LVPWs)、左室后壁舒張末期厚度(Left ventricular posterior wall width in diastole,LVPWd),左心室射血分?jǐn)?shù)(Left ventricular ejection fraction,LVEF)和左心室短軸縮短率(Left ventricular fraction shortening,LVFS)評價小鼠心臟結(jié)構(gòu)與功能。3.小鼠血壓測定在術(shù)前與術(shù)后,每周應(yīng)用小鼠鼠尾血壓儀測量各組小鼠收縮壓,根據(jù)收縮壓的平均值和標(biāo)準(zhǔn)差,應(yīng)用Graphpad軟件繪制時間-收縮壓折線圖。4.組織學(xué)染色將各組小鼠取材后的心臟制作石蠟切片,進(jìn)行HE和Masson染色,觀察心肌細(xì)胞形態(tài)、組織間隙膠原沉積情況,Masson染色半定量分析比較各組心臟標(biāo)本的膠原含量。5.小鼠心肌成纖維細(xì)胞分離培養(yǎng)本研究利用2-3日齡昆明小鼠乳鼠心臟,剪碎后經(jīng)膠原酶Ⅱ消化,利用差速貼壁法分離出小鼠心肌成纖維細(xì)胞。純化后培養(yǎng)于DMEM培養(yǎng)基中,選擇2-3代細(xì)胞用于實驗。6.細(xì)胞培養(yǎng)探討兩種GLP-1受體激動劑對AngⅡ刺激的小鼠心肌成纖維細(xì)胞、小鼠巨噬細(xì)胞RAW264.7和大鼠心肌細(xì)胞H9C2的作用。根據(jù)給予刺激不同進(jìn)行分組:對照組(無干預(yù))、AngⅡ組(AngⅡ10~(-6)mol/L)、AngⅡ+艾塞納肽組(AngⅡ10~(-6)mol/L+艾塞納肽100nmol/L)、AngⅡ+利拉魯肽組(AngⅡ10~(-6)mol/L+利拉魯肽100nmol/L),培養(yǎng)24h后收集細(xì)胞。7.細(xì)胞共培養(yǎng)應(yīng)用Transwell小室將小鼠巨噬細(xì)胞與心肌成纖維細(xì)胞共培養(yǎng),按步驟6中的分組進(jìn)行干預(yù),觀察巨噬細(xì)胞與成纖維細(xì)胞間的相互作用。8.蛋白印跡(Western blot)收集各組細(xì)胞,提取蛋白,分別檢測心肌細(xì)胞和成纖維細(xì)胞Ⅰ型膠原、Ⅲ型膠原、MMP-2和MMP-9的表達(dá)及巨噬細(xì)胞IL-6、IL-1β和TGF-β1的表達(dá)情況。9.統(tǒng)計學(xué)方法實驗數(shù)據(jù)的統(tǒng)計學(xué)分析應(yīng)用SPSS16.0軟件。連續(xù)變量資料以均數(shù)±標(biāo)準(zhǔn)差的形式表示。根據(jù)變量特點選擇Oneway ANOVA或LSD post-hoc來進(jìn)行多組數(shù)據(jù)間的變量比較。p0.05代表差異具有統(tǒng)計學(xué)顯著性意義。研究結(jié)果1.體重和血糖:在實驗結(jié)束時,AngⅡ+利拉魯肽組(26.18±1.40g)和AngⅡ+艾塞那肽組的小鼠體重(26.51±1.38g)比對照組(27.65±0.97g)稍下降(p0.05);4個小鼠實驗組之間的空腹血糖無差異(p0.05)。2.收縮壓的影響:在實驗結(jié)束時,AngⅡ+利拉魯肽組(139.0±2.9mm Hg)和AngⅡ+艾塞納肽組小鼠(141.7±5.4mm Hg)收縮壓均低于AngⅡ組(148.3±4.1mm Hg,p0.05),GLP-1受體激動劑干預(yù)組小鼠之間收縮壓無差異(p3.超聲心動圖指標(biāo):AngⅡ+利拉魯肽組的LVIDd、LVIDs、IVSd、LVPWd、LVEF和FS分別為3.59±0.38mm、2.01±0.26mm、0.59±0.08mm、0.82±0.05mm、76.3±3.06%、44.4±2.17%;AngⅡ+艾塞那肽組的LVIDd、LVIDs、IVSd、LVPWd、LVEF和FS分別為3.43±0.63mm、1.94±0.41mm、0.69±0.04mm、0.79±0.04mm、75.6±5.23%、44.3±2.75%;以上兩組的各指標(biāo)與AngⅡ組0.87±0.04mm、LVEF 64.5±4.62%和FS 35.5±3.24%)的均有差異(p0.05),GLP-1受體激動劑干預(yù)組小鼠之間上述指標(biāo)無差異(p0.05)。4.組織學(xué)HE染色和Masson染色:(1)HE染色切片顯示,與對照組相比,AngⅡ組心臟室壁增厚、心腔擴(kuò)大、心肌細(xì)胞肥大、排列紊亂、細(xì)胞間隙縮小;而利拉魯肽和艾塞那肽干預(yù)組的上述異常表觀較AngⅡ組輕。(2)Masson染色顯示,AngⅡ組切片染成藍(lán)色的膠原纖維含量明顯高于其余3組,半定量分析顯示利拉魯肽和艾塞那肽干預(yù)組切片的膠原含量低于AngⅡ組(p0.05),GLP-1受體激動劑干預(yù)組小鼠之間膠原含量無差異(p0.05)。5.GLP-1受體激動劑對大鼠心肌細(xì)胞的影響:細(xì)胞培養(yǎng)Western blot結(jié)果顯示,與對照組相比,AngⅡ組H9C2細(xì)胞MMP-2、MMP-9和Ⅲ型膠原表達(dá)量增加(p0.05);利拉魯肽和艾塞那肽干預(yù)后可抑制AngⅡ?qū)π募〖?xì)胞MMP-2和MMP-9表達(dá)的上調(diào)作用(p0.05)。6.GLP-1受體激動劑對小鼠巨噬細(xì)胞的影響:Western blot顯示,相比對照組,AngⅡ可上調(diào)小鼠巨噬細(xì)胞RAW264.7、促炎因子IL-6、IL-1β和TGF-β1的表達(dá)(p0.05);相比AngⅡ組,給予利拉魯肽和艾塞那肽干預(yù)后,巨噬細(xì)胞表達(dá)TGF-β1減少(p0.05)。7.GLP-1受體激動劑對小鼠心肌成纖維細(xì)胞的影響:Western blot顯示,相比對照組,AngⅡ刺激后心肌成纖維細(xì)胞表達(dá)Ⅰ型膠原、Ⅲ型膠原、MMP-2、MMP-9增多(p0.05);而相比AngⅡ組,上述蛋白在利拉魯肽和艾塞那肽干預(yù)組均無變化(p0.05)。8.GLP-1受體激動劑對與小鼠巨噬細(xì)胞共培養(yǎng)的小鼠心肌成纖維細(xì)胞的影響:Western blot顯示,和AngⅡ組相比,加入AngⅡ刺激的巨噬細(xì)胞可促進(jìn)成纖維細(xì)胞表達(dá)更多的膠原蛋白和MMP-2、MMP-9,而加入利拉魯肽和艾塞那肽干預(yù)AngⅡ刺激的巨噬細(xì)胞后,心肌成纖維細(xì)胞中Ⅰ型、Ⅲ型膠原、MMP-2、MMP-9的表達(dá)量減少(p0.05)。研究結(jié)論1.利拉魯肽和艾塞那肽能夠降低AngⅡ誘導(dǎo)的小鼠動物模型血壓升高的幅度,降壓幅度二者之間無差異,對小鼠的空腹血糖水平無影響;2.利拉魯肽和艾塞那肽能改善AngⅡ誘導(dǎo)的小鼠高血壓心臟纖維化模型的心臟肥厚、心腔擴(kuò)大、心功能減低和心臟間質(zhì)纖維化,并且二者之間無差別;3.利拉魯肽和艾塞那肽能夠抑制AngⅡ刺激下大鼠心肌細(xì)胞H9C2過量表達(dá)MMP-2、MMP-9以及小鼠巨噬細(xì)胞RAW264.7TGF-β1的過量表達(dá);對于AngⅡ誘導(dǎo)的小鼠心肌成纖維細(xì)胞過量表達(dá)MMP-2、MMP-9、Ⅰ型膠原、Ⅲ型膠原無抑制作用;4.利拉魯肽與艾塞那肽干預(yù)AngⅡ刺激的巨噬細(xì)胞與心肌成纖維細(xì)胞共培養(yǎng)可抑制心肌成纖維細(xì)胞中Ⅰ型、Ⅲ型膠原、MMP-2、MMP-9的表達(dá)。
[Abstract]:Background cardiac fibrosis can occur in all kinds of heart diseases, such as hypertension, ischemic heart disease and heart valvular disease. Current epidemiological data in China show that in recent years, the prevalence of hypertension in people over 15 years of age has reached 24%, the cumulative number of hypertensive patients is 266 million, and about 10 million of the new cases of hypertension are added each year. The treatment rate of hypertension (24.7%) and control rate (6.1%) are low. Hypertension has gradually become the main cause of cardiac fibrosis. The cardiac fibrosis caused by hypertension is manifested in the disorder of collagen synthesis and degradation in the cardiac tissue (including the degradation of the original collagen fibrous net and the oversynthesis of collagen fibers), and the abnormal collagen fibrils in the intercellular space of the cardiac myocytes Deposition, decline of ventricular wall compliance and cardiac hypertrophy, early diastolic dysfunction, gradually causing systolic dysfunction, and eventually leading to heart failure. Angiotensin II (Angiotensin II, Ang II) plays an important role in the pathophysiological process of hypertensive cardiac fibrosis, and Ang II passes through the Ang II type I receptor (Type I angi). Otensin II receptor, AT_1R) combined with contraction of vascular smooth muscle, activating inflammatory cells to induce inflammatory response, and stimulating fibroblasts to overexpress collagen induced collagen fibrous deposition of collagen to cause cardiac fibrosis. At present, the prevention and treatment drugs for Ang II induced hypertension mainly include angiotensin converting Enzyme inhibitors (Angiotensin converting enzymeinhibitor, ACEI) and AT_1R antagonists (Angiotensin II receptor blocker, ARB) are the two major drugs to reduce the formation of Ang II and inhibit AT_1R activation. Glucagon like peptide 1 is an enterostimulating hormone secreted by intestinal endocrine cells and is maintained. The human body plays an important role in postprandial blood glucose stability, but the endogenous GLP-1 secretion is rapidly degraded by the two peptidyl peptidase -4 (Dipeptidyl peptidase-4, DDP-4) in the body, and the half-life in the human body is only 1-2 minutes. Therefore, in order to prolong the half-life of the body, a GLP-1 receptor agonist, which should be used for the treatment of type 2 diabetes, is found. The clinical practice has found that GLP-1 receptor agonists have played an important role in improving human lipid metabolism, regulating vascular endothelial function, preventing arteriosclerosis and heart protection in addition to controlling blood sugar and improving insulin resistance in the treatment of diabetes, suggesting that these drugs can be used in type 2 diabetes. Animal experiments have shown that GLP-1 receptor agonists can reduce myocardial infarction area, reduce myocardial ischemia reperfusion injury, improve cardiac function, and improve the degree of cardiac fibrosis after myocardial infarction. In the Ang II induced hypertensive cardiac fibrosis model, GLP-1 receptor excitation Also, the role of GLP-1 receptor agonists in inhibiting cardiac fibrosis is also confirmed in patients with type 2 diabetes with heart failure, myocardial infarction, or hypertension. Lalalupin and alsasin peptide chain structure is different, and there is still a lack of research and comparison at present. The effect of two GLP-1 receptor agonists on hypertensive cardiac fibrosis is different, and the role of GLP-1 receptor agonists in different cells (cardiomyocytes, fibroblasts, macrophages) in the process of cardiac fibrosis is also rarely reported. In addition, whether GLP-1 receptor agonists can directly act on myocardial fibroblasts. This study will discuss the above 3 problems with lealulu and alenenin on Ang II induced hypertensive cardiac fibrosis in vitro culture cells and mouse models respectively. Purpose 1. the purpose of this study was to induce Ang II than lealulu and alenenin. The function of cardiac function and cardiac fibrosis in mice with hypertensive cardiac fibrosis; 2. the effects of lealulu and alenenin on the stimulation of cardiac myocytes, macrophages and fibroblasts in vitro were observed by Ang II. 3. by cell co culture, the cardiac fibrosis process was observed at the level of GLP-1 receptor agonists at the cell level. Method 1. animal model establishment and drug intervention of 40 healthy male C57BL/6J mice (body weight 21-26g) were randomly divided into 4 groups after 1 weeks of adaptive feeding. According to the group situation, the capsule osmotic pressure pump was implanted in the back of the mice: the control group was implanted osmotic pump containing physiological salt water, Ang II group, Ang II + L alalu group, Ang II + Arbor The peptide group implants the capsule osmotic pump containing Ang II to release Ang II 28d at a constant speed of 1.44mg/kg/d; Ang II + learalu group and Ang II + aleninin group were given the lialalu 0.4 mg/kg/d and the 0.1mg/kg/d intraperitoneal injection until the end of the experiment before the operation. After the experimental knot, the mice were weighed and the blood glucose test paper was detected. Fasting blood glucose, then euthanasia was executed in mice, and cardiac tissue specimens were left for.2. echocardiography to evaluate the echocardiographic examination of all mice at the end of the heart structure and function test, and the left ventricular end systolic diameter (Left ventricular internal dimension in systole, LVIDs) was measured by two-dimensional ultrasound and M ultrasound imaging technique. The end diastolic diameter of the left ventricle (Left ventricular internal dimension in diastole, LVIDd), the end systolic thickness of the ventricular septum (Interventricular septal width in systole), the end systolic thickness of the ventricular septum, and the end systolic thickness of the left ventricular wall DTH in systole, LVPWs), the end diastolic thickness of left ventricular posterior wall (Left ventricular posterior wall width in diastole, LVPWd), left ventricular ejection fraction and left ventricular short axis shortening rate in mice The mice tail blood pressure instrument was used to measure the systolic pressure of mice every week before and after the operation. According to the mean and standard deviation of the systolic pressure, the Graphpad software was used to draw the time contraction compression line graph.4. tissue staining to make paraffin sections of the hearts after the mice were obtained by HE and Masson staining, and to observe the morphology of the cardiac myocytes and the interstitial space. Collagen deposition, Masson staining and semi quantitative analysis were used to compare the collagen content of cardiac specimens in each group.5. mouse myocardial fibroblasts isolated and cultured. The heart of 2-3 day old Kunming mice was used to digest the rat heart. After the digestion of collagenase II, the murine myocardial fibroblasts were isolated by the differential adherence method, and then cultured in the DMEM medium. 2-3 generation cells were selected for experimental.6. cell culture to explore the effect of two GLP-1 receptor agonists on Ang II stimulated murine myocardial fibroblasts, mouse macrophages RAW264.7 and rat cardiac myocyte H9C2. The control group was divided into groups: the control group (no intervention), the Ang II Group (Ang II 10~ (-6) mol/L), Ang II + Senna peptide group (Ang) II 10~ (-6) mol/L+ Senna peptide 100nmol/L), Ang II + L alalu peptide group (Ang II 10~ (-6) mol/L+ alalu peptide 100nmol/L). After culture 24h, the cell.7. cells were co cultured and used to co culture mouse macrophages and myocardial fibroblasts, and they were intervened in step 6 and observed between macrophages and fibroblasts. Interaction.8. Western blot (Western blot) was used to collect all the cells and extract protein. The expression of type I collagen, collagen type III, MMP-2 and MMP-9 in cardiomyocytes and fibroblasts and the expression of IL-6, IL-1 beta and TGF- beta 1 in macrophage, IL-6, IL-1 beta and TGF- beta 1 were used for statistical analysis of the statistical analysis of SPSS16.0 software. Oneway ANOVA or LSD post-hoc was selected according to the variable characteristics to compare the variables between the multiple groups of data. The.P0.05 representation difference was statistically significant. The results of the study were 1. weight and blood sugar: at the end of the experiment, the mice of Ang II + learalu group (26.18 + 1.40g) and Ang II + alisin group The body weight (26.51 + 1.38g) was slightly lower than that of the control group (27.65 0.97g) (P0.05), and the effect of the fasting blood glucose (P0.05).2. systolic pressure between the 4 experimental groups: at the end of the experiment, the systolic pressure of the Ang II + alaru group (139 + 2.9mm Hg) and the Ang II + alSenna peptide group (141.7 + 5.4mm Hg) was lower than that of the Ang II Group (148.3 +. There was no difference in systolic pressure between mice in the LP-1 receptor agonist group (p3. echocardiography: LVIDd, LVIDs, IVSd, LVPWd, LVEF and FS were 3.59 + 0.38mm, 2.01 + 0.26mm, 0.59 + 0.08mm, 0.82 +, 76.3 + 3.06%, 44.4 + 2.17%, 3.43 + 0, respectively. .63mm, 1.94 + 0.41mm, 0.69 + 0.04mm, 0.79 + 0.04mm, 75.6 + 5.23%, 44.3 + 2.75%, and the indexes of the above two groups were different from Ang II Group 0.87 + 0.04mm, LVEF 64.5 + 4.62% and FS 35.5 + 3.24%. There was no difference between the GLP-1 receptor agonist intervention group and the mice. Compared with the control group, the cardiac ventricular wall in the Ang II group was thickened, the heart cavity enlarged, the cardiac myocytes hypertrophy, disorder and the gap narrowed, while the above abnormality was lighter than the Ang II group. (2) Masson staining showed that the content of the blue collagen fiber in the Ang II group was significantly higher than the other 3 groups, half quantified. The collagen content of the sliced group of lialalu and aleninin intervention group was lower than that of the Ang II Group (P0.05). There was no difference in the collagen content between the mice of the GLP-1 receptor agonist intervention group (P0.05) and the effect of.5.GLP-1 receptor agonist on the rat cardiac myocytes: the cell culture Western blot results showed that the H9C2 cell MMP-2, MMP-9 of the Ang II group was compared with the control group. The expression of collagen type III and type III increased (P0.05), and the effects of Ang II on the expression of MMP-2 and MMP-9 (P0.05).6.GLP-1 receptor agonist on murine macrophages were inhibited by learalu and alenenin: Western blot showed that Ang II could increase RAW264.7, IL-6, IL-1 beta, and IL-1 beta in mice compared with the control group And the expression of TGF- beta 1 (P0.05); compared with the Ang II group, the effects of the macrophage on the expression of TGF- beta 1 decreased (P0.05).7.GLP-1 receptor agonists on the myocardial fibroblasts in the Ang II Group: Western blot showed that compared with the control group, the myocardial fibroblasts expressed type I collagen, type III collagen, MMP-2, MMP after Ang II stimulation. -9 increased (P0.05), but compared with the Ang II group, the above protein in the lialalu peptide and the alenenin intervention group had no change (P0.05) the effect of.8.GLP-1 receptor agonist on murine myocardial fibroblasts co cultured with mouse macrophages: Western blot showed that the macrophages added to the Ang II stimulated macrophage can promote fibroblast cell surface compared with the Ang II group. More collagen and MMP-2, MMP-9, and the expression of type I, type III collagen, MMP-2, MMP-9 in myocardial fibroblasts decreased (P0.05) after adding lealupeptide and alenenin to Ang II stimulated macrophages (P0.05). Conclusion 1. lealaru and alenenin could reduce the elevation of blood pressure in the mouse model induced by Ang II. There was no difference between the two degrees and the amplitude of blood pressure, and there was no effect on the level of fasting blood glucose in mice. 2. lalalu and aleninin could improve the cardiac hypertrophy, enlargement of heart cavity, decrease of heart function and interstitial fibrosis in the model of Ang II induced hypertensive cardiac fibrosis in mice, and there was no difference between the two and 3. llalupeptis and aleninin. The overexpression of H9C2 overexpression of MMP-2, MMP-9 and RAW264.7TGF- beta 1 of murine macrophages was inhibited by Ang II stimulation, and the excess expression of MMP-2, MMP-9, type I collagen and type III collagen in murine myocardial fibroblasts induced by Ang II was not inhibited; 4. lyalurin and alenenin interfered with the macrophages and macrophages stimulated by Ang II. Co culture of cardiac fibroblasts inhibited the expression of type I, III collagen, MMP-2 and MMP-9 in cardiac fibroblasts.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R541.3

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