【摘要】：背景:急性心肌梗死(Acute myocardial infarction,AMI)的大多數(shù)病因是不穩(wěn)定動脈粥樣硬化斑塊破裂形成血栓,從而中斷冠狀動脈血流。而AMI發(fā)病起始和發(fā)展過程中大量炎癥因子相互作用的參與是重要因素。盡管現(xiàn)在患者使用抗栓藥物或者采用冠狀動脈介入治療方法能早期使血管再通或使心肌再灌注,但是很多患者還會發(fā)生不同程度的左室重構,甚至心力衰竭。其中受損或梗死心肌細胞釋放炎癥因子,進而引發(fā)的炎癥反應在心肌重構和心肌纖維化中起到了重要作用。為抑制或減少斑塊發(fā)生和發(fā)展,今后防治冠心病的關鍵環(huán)節(jié)之一是抑制炎性反應等不利因素,然而,針對這些病理環(huán)節(jié)的治療,目前尚未有公認的藥物和其他有效的方法。曾有報道顯示阿托伐他汀在治療冠心病等心血管病過程中也發(fā)揮抗炎、抗氧化和抗纖維化等多樣化效應,但阿托伐他汀對AMI大鼠心肌炎癥及纖維化發(fā)展過程是否具有有益作用,其是否影響AMI大鼠心功能和血流動力學狀態(tài)尚待驗證,阿托伐他汀否通過調(diào)控TGF-β-smad和notch1信號通路起到上述有益作用尚還未知。此外,冠心病患者血漿炎性和纖維化因子半乳糖凝集素-3(Galectin-3)變化和他汀對Galectin-3的作用以及心房顫動(Atrial Fibrillation,AF)患者射頻消融(radiofrequency ablationradiofrequency,RFCA)前后Galectin-3變化均尚未見報道。目的:1、觀察大鼠AMI建模后第一天心功能變化及建模后第5天阿托伐他汀或氯沙坦鉀治療對大鼠血漿炎癥因子TNF-α,IL-1β的作用;2、觀察阿托伐他汀或氯沙坦鉀治療對大鼠AMI建模后第14天心功能和血流動力學影響,以及對心肌細胞外基質(zhì)金屬蛋白酶mmp2、mmp9及其抑制物TIMP2蛋白表達和血漿心功能標志物BNP的變化;3、觀察大鼠AMI建模后第28天,阿托伐他汀或氯沙坦鉀治療對大鼠的心功能和血流動力學影響,觀察心肌膠原蛋白CollagenⅠ、CollagenⅢ和notch1、TGF-β1、Smad2、Smad7、Galectin-3蛋白表達及血漿BNP變化;觀察阿托伐他汀或氯沙坦鉀是否通過抑制notch1-TGF-β-smad信號通路抑制AMI大鼠心肌炎癥和纖維化反應;4、觀察阿托伐他汀或氯沙坦鉀對AMI大鼠建模后第14天、28天心肌細胞結(jié)構和心肌膠原纖維的影響;5、臨床試驗:觀察冠心病患者包括穩(wěn)定心絞痛組(Stable angina pectoris,SAP)、不穩(wěn)定心絞痛組(Unstable angina pectoris,UAP)和AMI患者血漿炎性因子Galectin-3變化及與病情嚴重程度的相關關系,觀察阿托伐他汀80mg對AMI患者短期治療前后Galectin-3變化;觀察心房顫動(Atrial Fibrillation,AF)患者射頻消融(radiofrequency ablationradiofrequency,RFCA)前后Galectin-3變化。方法:1、大鼠分為四組:對照組(假手術組):單純分離前降支,未行結(jié)扎;心肌梗死組(AMI建模組):單純結(jié)扎冠狀動脈前降支,建模后無藥物治療;他汀組:前降支結(jié)扎+阿托伐他汀(10mg/kq/d)治療;氯沙坦組:前降支結(jié)扎+氯沙坦鉀治療(5mg/kq/d)。除對照組大鼠外,其余組入選大鼠EF均≤50%,評價建模后各組大鼠第14天、28天心功能和血流動力學變化,并觀察AMI后大鼠心肌細胞炎癥、纖維化發(fā)展變化過程。2、采用Elisa方法觀察大鼠AMI建模第5天血漿炎癥因子TNF-α、IL-1β變化和建模后第14天、28天血漿BNP變化。3、采用生物學Q-PCR、western blot技術和/或免疫組化方法檢測大鼠AMI建模后心肌細胞炎癥因子TNF-α、IL-1β、Galectin-3、心肌膠原蛋白CollagenⅠ、CollagenⅢ、金屬基質(zhì)蛋白酶mmp2、mmp9及其抑制物TIMP2和信號通路蛋白notch1、TGF-β1、Smad2、Smad7,觀察其變化。4、采用HE染色和MASSON染色觀察大鼠AMI建模后第14天、28天不同組大鼠心肌細胞結(jié)構變化和心肌膠原纖維變化。5、臨床試驗:采用Elisa方法測定不同冠心病類型患者和AF患者RFCA前后血漿炎性因子Galectin-3含量。AMI患者經(jīng)皮冠狀動脈介入(percutaneous coronary intervention,PCI)術前給予80mg阿托伐他汀治療,用Elisa方法測定對AMI患者PCI前后Galectin-3變化;觀察冠心病患者血漿Galectin-3水平與LVEF相關性。結(jié)果:1、大鼠AMI建模后24h心功能明顯下降,EF、FS值低于正常對照組;大鼠AMI建模后第5天血漿炎癥因子TNF-α、IL-1β升高,用阿托伐他汀或氯沙坦鉀治療后明顯下降(p0.05);2、大鼠AMI建模后第14天,阿托伐他汀組或氯沙坦鉀治療組心功能均較AMI未治療組提高,血流動力學指標dp/dt Max、dp/dtMin等明顯好轉(zhuǎn)(p0.05);應用Q-PCR和/或WesternBlot技術和/或免疫組化方法所檢測結(jié)果顯示,阿托伐他汀組或氯沙坦治療組大鼠心肌mmp2、mmp9、TNF-α、IL-1β蛋白表達降低,TIMP2蛋白表達增加(p0.05);建模14天后血漿心功能標志物BNP升高,阿托伐他汀組或氯沙坦治療組大鼠血漿BNP降低(p0.05)。3、大鼠AMI建模28天后,阿托伐他汀組或氯沙坦治療組心功能均較AMI未治療組提高,血流動力學指標dp/dt max、dp/dt min等明顯好轉(zhuǎn)(p0.05);應用Q-PCR和/或WesternBlot技術和/或免疫組化方法所檢測結(jié)果顯示,阿托伐他汀或氯沙坦抑制大鼠心肌膠原蛋白CollagenⅠ、CollagenⅢ表達(p0.05),并抑制notch1、TGF-β1、Smad2、Galectin-3蛋白表達,增加蛋白Smad7表達(p0.05);阿托伐他汀或氯沙坦通過抑制notch1-TGF-β-smad信號通路抑制AMI大鼠心肌炎癥和纖維化反應;建模28天后血漿心功能標志物BNP升高,阿托伐他汀組和氯沙坦治療組大鼠血漿BNP降低(p0.05);4、AMI大鼠建模14天和28天后,阿托伐他汀組或氯沙坦治療組心肌細胞結(jié)構紊亂現(xiàn)象好轉(zhuǎn),炎癥細胞減少,心肌膠原纖維組織范圍減少;5、臨床試驗顯示:AMI組患者血漿Galectin-3含量高于UAP組(p0.05),UAP組患者Galectin-3含量高于SAP組(p0.05);冠狀動脈多支病變組患者Galectin-3水平高于單只病變組(p0.05);AF行RFCA術后轉(zhuǎn)復為竇性心律患者Galectin-3水平較術前有所下降,但前后比較無差別(p0.05);AMI患者PCI術前給予80mg阿托伐他汀治療可降低血漿Galectin-3水平,但前后比較無差別;Galectin-3水平與冠心病患者左室射血分數(shù)(Left ventricular ejection fraction,LVEF)值成負相關性(r=-0.405,p0.05)。結(jié)論:1、大鼠AMI建模后心肌發(fā)生炎癥、纖維化反應、炎癥因子TNF-α、IL-1β、Galectin-3升高和纖維化因子mmp2、mmp9、CollagenⅠ、CollagenⅢ升高,同時心功能受損,心室發(fā)生重構,而阿托伐他汀或氯沙坦可通過notch1-TGF-β-smads通路抑制心肌炎癥及纖維化,減少炎癥及纖維化指標表達,減輕心肌重構,在一定程度上對心功能和血流動力學起到改善作用。2、阿托伐他汀或氯沙坦可改善AMI大鼠建模后心肌細胞壞死和結(jié)構紊亂,并較少心肌膠原纖維范圍;3、臨床試驗顯示,冠心病患者血漿中炎癥和纖維化因子Galectin-3含量與心肌缺血、損傷嚴重程度相關,隨著心肌缺血、損傷加重,Galectin-3含量逐步升高;Galectin-3與冠心病患者LVEF成負性相關;4、Galectin-3是心肌炎癥和纖維化因子,AF患者Galectin-3水平升高與心房纖維化有關,RFCA術后Galectin-3水平有所下降,但術前術后比較無差別,可能與樣本量較少有關;阿托伐他汀降低AMI患者PCI術后Galectin-3水平,但前后比較無差別,可能與服藥次數(shù)較少有關。
[Abstract]:BACKGROUND: Most of the causes of acute myocardial infarction (AMI) are unstable atherosclerotic plaque rupture, resulting in thrombosis, which interrupts coronary flow. The involvement of a large number of inflammatory factors in the initiation and development of AMI is an important factor, although patients now use antithrombotic drugs or take them. Coronary artery interventional therapy can early revascularize or reperfusion myocardium, but many patients also have different degrees of left ventricular remodeling, and even heart failure. Injured or infarcted myocardial cells release inflammatory factors, which in turn trigger inflammatory reactions in myocardial remodeling and myocardial fibrosis play an important role. To prevent or reduce the occurrence and development of plaque, one of the key links in the prevention and treatment of coronary heart disease in the future is to inhibit inflammatory reaction and other adverse factors. However, there are no recognized drugs and other effective methods for the treatment of these pathological links. It has been reported that atorvastatin also plays an anti-inflammatory role in the treatment of cardiovascular diseases such as coronary heart disease. However, whether atorvastatin has beneficial effects on the development of myocardial inflammation and fibrosis in AMI rats, and whether it affects cardiac function and hemodynamic status in AMI rats remains to be verified. Whether atorvastatin plays the above beneficial role by regulating TGF-beta-smad and Notch1 Signaling pathways remains to be determined. In addition, the changes of plasma inflammatory and fibrotic factors galectin-3 (Galectin-3) and the effect of statin on Galectin-3 in patients with coronary heart disease and the changes of Galectin-3 in patients with atrial fibrillation (AF) before and after radiofrequency ablation (RFCA) have not been reported. Changes of cardiac function on the first day after modeling and effects of atorvastatin or losartan potassium on plasma inflammatory factors TNF-a and IL-1 beta in rats on the fifth day after modeling; 2. Effects of atorvastatin or losartan potassium on cardiac function and hemodynamics and extracellular matrix metalloproteinase mmp2, MMP9 in rats with AMI on the fourteenth day after modeling were observed. The expression of TIMP2 protein and the changes of plasma cardiac function marker BNP were observed. 3. The effects of atorvastatin or losartan potassium on cardiac function and hemodynamics were observed on 28 days after AMI in rats, and the expressions of collagen I, Collagen III and notch1, TGF-beta 1, Smad2, Smad7, Galectin-3 protein and plasma BN were observed. To observe whether atorvastatin or losartan potassium can inhibit myocardial inflammation and fibrosis in rats with AMI by inhibiting notch1-TGF-beta-smad signaling pathway; 4. To observe the effects of atorvastatin or losartan potassium on myocardial cell structure and myocardial collagen fibers in rats with AMI on the 14th and 28th days after modeling; 5. Clinical trial: To observe the patients with coronary heart disease. The changes of plasma inflammatory factor Galectin-3 in patients with stable angina pectoris (SAP), unstable angina pectoris (UAP) and AMI and their correlation with the severity of the disease were observed. The changes of Galectin-3 in patients with AMI before and after treatment with atorvastatin 80 mg were observed. Methods: 1. Rats were divided into four groups: control group (sham operation group): isolated anterior descending branch without ligation; myocardial infarction group (AMI modeling group): ligation of anterior descending branch of coronary artery without drug therapy; statin group: ligation of anterior descending branch + atrovir Statin (10mg/kq/d) treatment; Losartan group: anterior descending branch ligation + losartan potassium treatment (5mg/kq/d). Except for the control group rats, the EF of the other groups were all less than 50%. The changes of cardiac function and hemodynamics were evaluated on the 14th and 28th day after modeling, and the changes of myocardial inflammation and fibrosis were observed after AMI. 2. Elisa method was used. The changes of plasma inflammatory factors TNF-a, IL-1 beta and BNP were observed on the fifth day after AMI modeling and on the fourteenth and twenty-eighth days after AMI modeling. 3. Biological Q-PCR, Western blot and/or immunohistochemical methods were used to detect the levels of inflammatory factors TNF-a, IL-1 beta, Galectin-3, Collagen I, Collagen III and metal matrix in myocardial cells of rats after AMI modeling. Proteinase MMP 2, MMP 9 and their inhibitors TIMP 2 and signal pathway proteins notch 1, TGF - beta 1, Smad 2, Smad 7 were observed. 4. HE staining and MASSON staining were used to observe the changes of myocardial cell structure and myocardial collagen fibers in different groups of rats on the 14th and 28th days after AMI modeling. 5. Clinical trial: Elisa method was used to determine different types of coronary heart disease. Levels of plasma inflammatory factor Galectin-3 in patients with type I and AF before and after RFCA were measured by Elisa method. Results: 1, 24 hours after AMI, the cardiac function of rats decreased significantly, EF, FS values were lower than the normal control group; 5 days after AMI, the plasma inflammatory factors TNF-a, IL-1 beta increased, and significantly decreased after treatment with atorvastatin or losartan potassium (p0.05); 2, 14 days after AMI, the cardiac function of atorvastatin group or losartan potassium treatment group were significantly lower than that of AMI untreated rats. The results of Q-PCR and/or Western Blot and/or immunohistochemistry showed that the expression of mmp-2, mmp-9, TNF-alpha, IL-1 beta protein in myocardium of rats in atorvastatin group or losartan treatment group decreased, and the expression of TIMP-2 protein increased 14 days after modeling (p0.05). Plasma BNP was elevated, plasma BNP was decreased in atorvastatin group or losartan treatment group (p0.05). After 28 days of AMI modeling, cardiac function in atorvastatin group or losartan treatment group was improved, and hemodynamic indexes such as dp/dt max, dp/dt min were improved significantly (p0.05). And/or immunohistochemical staining showed that atorvastatin or losartan inhibited the expression of collagen Collagen I and Collagen III in rat myocardium (p0.05), inhibited the expression of notch 1, TGF-beta 1, Smad2, and Galectin-3, and increased the expression of Smad7 (p0.05); atorvastatin or losartan inhibited the notch 1-TGF-beta-smad signaling pathway by inhibiting the expression of Smad7 (p0.05). Myocardial inflammation and fibrosis in AMI rats were induced; plasma BNP increased after 28 days of modeling, plasma BNP decreased in atorvastatin group and losartan group (p0.05); 4. After 14 and 28 days of modeling, the structural disorder of myocardial cells in atorvastatin group or losartan group improved, inflammatory cells decreased, and myocardial glue decreased. 5, clinical trials showed that the level of Galectin-3 in plasma of AMI patients was higher than that of UAP patients (p0.05), and the level of Galectin-3 in UAP patients was higher than that of SAP patients (p0.05); the level of Galectin-3 in coronary artery disease group was higher than that of single lesion group (p0.05); the level of Galectin-3 in AF patients converted to sinus rhythm after RFCA was higher than that before operation. The level of Galectin-3 was negatively correlated with the left ventricular ejection fraction (LVEF) in patients with coronary artery disease (r = - 0.405, P 0.05). Conclusion: 1. Rat AMI was established. Inflammation, fibrosis, elevation of inflammatory factors TNF-alpha, IL-1beta, Galectin-3 and fibrosis factors mmp2, mmp9, Collagen I and Collagen III occur in the myocardium after cardiac infarction. Atorvastatin or losartan can inhibit myocardial inflammation and fibrosis through notch1-TGF-beta-smads pathway and reduce inflammation and fibrosis. Atorvastatin or losartan can improve myocardial cell necrosis and structural disorder in AMI rats, and less myocardial collagen fibers range; 3. Clinical trials showed that inflammation and fibrosis factor Gale in plasma of patients with coronary heart disease. The content of ctin-3 was correlated with the severity of myocardial ischemia and injury, with the increase of myocardial ischemia, the content of Galectin-3 increased gradually; Galectin-3 was negatively correlated with LVEF in patients with coronary heart disease; 4, Galectin-3 was a factor of myocardial inflammation and fibrosis; the elevation of Galectin-3 in AF patients was related to atrial fibrosis, and the level of Galectin-3 decreased after RFCA. Atorvastatin decreased the level of Galectin-3 in patients with AMI after PCI, but there was no difference before and after PCI, which may be related to the fewer times of taking drugs.
【學位授予單位】：天津醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R542.22

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10 劉佳琦;胡大海;張戰(zhàn)鳳;官浩;折濤;張軍;白曉智;;IFN-γ對瘢痕疙瘩成纖維細胞TGF-β/Smad信號通路作用的研究[A];中華醫(yī)學會燒傷外科學分會2009年學術年會論文匯編[C];2009年

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