本文選題：皮質(zhì)酮 + 心肌肥大��； 參考：《暨南大學(xué)》2016年碩士論文

【摘要】：流行病學(xué)研究表明,胎兒時期不良的宮內(nèi)環(huán)境會導(dǎo)致成年期高血壓、心臟肥大、胰島素抵抗(Insulin resistance,IR)、2型糖尿病和精神心理障礙等一系列疾病的風(fēng)險增加。孕婦產(chǎn)前應(yīng)激狀態(tài)下,大量分泌的皮質(zhì)激素(Corticosteroides),能夠直接或間接通過胎盤屏障進(jìn)入宮內(nèi)影響胚胎發(fā)育。近年來更有大量的動物試驗及臨床研究表明,妊娠期過度的糖皮質(zhì)激素(Glucocorticoid,GC)暴露與胎兒生長受限、成年期心血管及內(nèi)分泌代謝等系統(tǒng)性疾病的發(fā)生發(fā)展密切相關(guān),其中對于心臟的副作用更是包括了短期和長期的影響,因此成為目前研究的關(guān)注點之一。然而,關(guān)于類固醇皮質(zhì)激素對胚胎心臟發(fā)育的影響及損傷機制尚未深入闡明。同時,考慮到目前用于研究產(chǎn)前皮質(zhì)類激素暴露對胚胎發(fā)育影響過程中胎生動物模型存在胚胎內(nèi)環(huán)境無法接觸的局限性。因此,本課題將分別采用雞胚模型觀察應(yīng)激激素皮質(zhì)酮(Corticosterone,CORT)對胚胎心臟發(fā)育的影響,并結(jié)合CORT負(fù)荷H9C2細(xì)胞模型研究和探討其內(nèi)在的分子機理。首先,我們建立CORT負(fù)荷誘導(dǎo)心臟發(fā)育障礙的雞胚模型。通過向EDD3(Embryo development day 3)雞胚氣室隔天注射一系列濃度的CORT(0.5、2.5、5、10 nmol/egg),模擬胚胎生長的高皮質(zhì)類激素暴露環(huán)境,繼續(xù)孵育至EDD14結(jié)束。為確定外源性注射的CORT能夠進(jìn)入胚胎體內(nèi)影響心臟發(fā)育,我們通過HPLC-UV方法檢測胚胎血漿中CORT的含量,并對胚體及心臟進(jìn)行稱重,統(tǒng)計心臟的相對重量、死亡率等指標(biāo)。體視鏡下觀察胚胎心臟的外部形態(tài)特征并拍照,經(jīng)固定、包埋、切片及HE病理染色觀察胚胎心臟的內(nèi)部結(jié)構(gòu)變化。實驗結(jié)果顯示,外源性注射的CORT能夠被雞胚吸收,血漿中CORT水平顯著上升,導(dǎo)致胚胎死亡率增加、生長發(fā)育遲緩、而心臟相對重量卻顯著上升,且一定范圍內(nèi)與CORT濃度呈劑量相關(guān)性。在此基礎(chǔ)上我們選擇了CORT 2.5 nmol和5 nmol進(jìn)行后續(xù)實驗。形態(tài)學(xué)結(jié)果顯示,CORT負(fù)荷雞胚胎的心臟整體體積增大并伴隨有心室腔擴大、室壁變薄,室壁心肌細(xì)胞密度降低、間距增大等內(nèi)部形態(tài)特征,同時進(jìn)一步麥胚凝集素(Wheat germ agglutinin,WGA)染色結(jié)果顯示單個心肌細(xì)胞橫截面積明顯增大。為進(jìn)一步觀察CORT對心臟病理學(xué)變化的影響,通過超聲心動圖(Echocardiography)評價其心臟功能狀況,檢測結(jié)果顯示CORT導(dǎo)致胚胎心臟收縮功能下降,表現(xiàn)為射血分?jǐn)?shù)和短軸縮短率顯著下降。通過免疫熒光標(biāo)記技術(shù),我們發(fā)現(xiàn)CORT負(fù)荷能夠抑制心肌細(xì)胞的增殖、促進(jìn)心肌細(xì)胞凋亡的發(fā)生,同時增加心臟肌球蛋白的表達(dá)。RT-PCR檢測結(jié)果亦發(fā)現(xiàn),經(jīng)CORT作用后心臟肌動蛋白(Actinαcardiac muscle l,ACTC-1)的mRNA水平顯著升高。以上結(jié)果提示,cort能夠抑制心肌細(xì)胞增殖而促進(jìn)凋亡,刺激細(xì)胞向肥大表型轉(zhuǎn)變,造成心臟異常肥大,收縮功能降低�；谛呐K組織代謝活躍、能量需求高、線粒體含量豐富等特點,臨床上一系列心臟疾病的發(fā)生發(fā)展均與線粒體代謝功能異常息息相關(guān)。相關(guān)研究表明,線粒體功能異常被認(rèn)為是促進(jìn)心肌病理肥大變化及向心衰轉(zhuǎn)變的主要發(fā)病機理之一。為此,本課題進(jìn)一步研究了cort對雞胚心肌組織中線粒體功能的影響。向edd3雞胚氣室隔天注射cort(2.5和5nmol)后,孵育至edd14取雞胚心臟組織,使用線粒體分離試劑盒提取心肌細(xì)胞線粒體,采用流式細(xì)胞儀檢測線粒體膜電位ψm及通過熒光酶標(biāo)儀實時監(jiān)測線粒體內(nèi)ros的生成速率,hplc法測定肥大心肌組織中能量物質(zhì)atp含量變化。此外,利用試劑盒分別對心肌組織內(nèi)氧化和抗氧化能力指標(biāo)、線粒體呼吸鏈復(fù)合物活性進(jìn)行測定。結(jié)果顯示,cort負(fù)荷能夠顯著影響雞胚心肌細(xì)胞的線粒體功能,具體表現(xiàn)為ψm下降、ros產(chǎn)生速率增加、atp含量顯著下降,脂質(zhì)過氧化產(chǎn)物mda含量增加而抗氧化酶mnsod活性和抗氧化分子gsh/gssg相對量卻顯著降低。同時,cort負(fù)荷也會導(dǎo)致雞胚心肌細(xì)胞中線粒體呼吸鏈復(fù)合物活性iii、iv、v顯著下降。此外,通過透射電鏡我們還觀察到雞胚注射cort后,心肌細(xì)胞中的線粒體出現(xiàn)聚集呈簇等異�，F(xiàn)象。以上結(jié)果提示,cort負(fù)荷會導(dǎo)致雞胚心肌細(xì)胞中線粒體形態(tài)及功能異常。線粒體融合蛋白2(mitofusin2,mfn2)蛋白是一種介導(dǎo)線粒體融合的重要蛋白,參與維持線粒體動力學(xué)平衡及結(jié)構(gòu)穩(wěn)態(tài)。近期有研究在嚙齒類動物應(yīng)激模型中發(fā)現(xiàn),應(yīng)激產(chǎn)生的激素cort能夠通過調(diào)控mfn2表達(dá)而影響腦組織的線粒體結(jié)構(gòu)及功能。因此,我們猜想cort負(fù)荷導(dǎo)致胚胎心臟發(fā)育紊亂且伴隨線粒體功能障礙是否涉及mfn2的表達(dá)異常。利用westernblotting檢測雞胚心肌組織mfn2蛋白表達(dá)變化,結(jié)果表明,cort負(fù)荷組雞胚心肌組織中mfn2蛋白表達(dá)水平較對照組明顯上調(diào)。為了進(jìn)一步驗證cort引起心肌細(xì)胞肥大確實是與mfn2介導(dǎo)的線粒體功能缺陷有關(guān),本課題采用cort(200μm,48h)負(fù)荷大鼠胚胎心肌細(xì)胞h9c2建立體外模型,實驗分為control、cort以及cort+gr拮抗劑(ru486)三組,觀察cort對h9c2細(xì)胞形態(tài)的影響,mfn2蛋白水平以及線粒體膜電位的變化,同時通過westernblotting檢測細(xì)胞水平凋亡相關(guān)蛋白的表達(dá)情況。最后在單獨轉(zhuǎn)染過表達(dá)mfn2蛋白情況下,檢測其對心肌細(xì)胞結(jié)構(gòu)及凋亡的影響,進(jìn)一步驗證cort導(dǎo)致心臟肥大發(fā)育異常是通過調(diào)控mfn2而實現(xiàn)的。結(jié)果顯示,h9c2細(xì)胞經(jīng)cort作用后,出現(xiàn)與雞胚實驗相同的結(jié)果,cort能夠?qū)е滦募〖?xì)胞體積變大,細(xì)胞水平mfn2蛋白表達(dá)上調(diào),線粒體膜電位ψm降低以及bcl-2蛋白家族Bax/Bcl-2相對水平增加,心肌細(xì)胞凋亡增加。在提前給予GR拮抗劑(Ru486,10μM)基礎(chǔ)上再經(jīng)CORT作用,上述變化均可得到相應(yīng)的改善,提示CORT可能通過GR介導(dǎo)以上心肌細(xì)胞結(jié)構(gòu)及凋亡的改變。同時在轉(zhuǎn)染過表達(dá)Mfn2后,凋亡蛋白Bax/Bcl-2顯著增加,活化的Caspase3蛋白表達(dá)增多以及心肌細(xì)胞肥大基因SKA的mRNA水平上升,說明CORT可通過調(diào)控Mfn2表達(dá)進(jìn)而損傷線粒體、促進(jìn)細(xì)胞凋亡,致使心室壁細(xì)胞數(shù)目減少,最終引起心臟發(fā)育損傷、異常肥大。綜上,CORT通過調(diào)控Mfn2介導(dǎo)心肌線粒體功能障礙,導(dǎo)致心肌能量代謝異常、ROS產(chǎn)生過多并且促進(jìn)心肌細(xì)胞凋亡,最終引發(fā)心臟發(fā)育異常肥大,從而為防治此類相關(guān)心臟疾患提供新的治療靶點和理論依據(jù)。
[Abstract]:Epidemiological studies have shown that the undesirable intrauterine environment in the fetal period can lead to adult hypertension, cardiac hypertrophy, insulin resistance (Insulin resistance, IR), the increased risk of a series of diseases such as type 2 diabetes and mental disorder. In pregnant women, a large amount of corticosteroids (Corticosteroides) can be produced directly or between antenatal stressful state. In recent years, a large number of animal experiments and clinical studies have shown that excessive Glucocorticoid (GC) exposure in pregnancy is closely related to the development of fetal growth restriction, cardiovascular and endocrine metabolism in adulthood, including the side of the heart. However, the effect of steroid corticosteroids on fetal heart development and the mechanism of injury have not yet been clarified. Meanwhile, the existence of a fetal animal model in the study of the effects of prenatal corticosteroid exposure on embryonic development is considered. Therefore, we will use the chicken embryo model to observe the effect of Corticosterone (CORT) on the development of fetal heart, and to study and explore the intrinsic molecular mechanism of the CORT load H9C2 cell model. First, we establish the chicken embryo with CORT load induced cardiac dysplasia. Model. By injecting a series of concentrations of CORT (0.5,2.5,5,10 nmol/egg) into the EDD3 (Embryo development day 3) chicken embryo gas chamber every other day to simulate the exposure environment of the high corticosteroid growth of the embryo and continue to incubate to the end of EDD14. In order to determine that the exogenous CORT can enter the fetal body and affect the heart development, we examine the HPLC-UV method. The content of CORT in the plasma of the embryo was measured, and the embryo body and heart were weighed, the relative weight of the heart, the mortality and so on. The external morphological features of the embryonic heart were observed under the body view mirror and photographed. The changes of the internal structure of the embryonic heart were observed by fixed, embedded, sliced and HE pathological staining. The experimental results showed that the exogenous CORT could be injected. The level of CORT in plasma increased significantly, resulting in increased embryo mortality and growth retardation, while the relative weight of the heart increased significantly, and a dose correlation with the concentration of CORT in a certain range. On this basis we chose CORT 2.5 nmol and 5 nmol for follow-up experiments. Morphological results showed that CORT load chicken embryos The overall volume of the heart increased with the enlargement of the ventricular chamber, the thinner wall of the ventricle, the decrease of the cell density and the increase of the space between the ventricular wall, and the further staining of Wheat germ agglutinin (WGA) showed that the cross sectional area of the single cardiac myocytes increased clearly. To further observe the pathological changes of the heart in CORT The results of echocardiography (Echocardiography) were used to evaluate the cardiac function status. The results showed that CORT resulted in a decrease in the systolic function of the embryonic heart, which showed a significant decrease in the ejection fraction and short axis shortening. We found that the CORT load could inhibit the proliferation of cardiac myocytes and promote the apoptosis of cardiac myocytes by immunofluorescent labeling technique. At the same time, the expression of cardiac myosin expression.RT-PCR detection results also found that the mRNA level of Actin alpha cardiac muscle L (ACTC-1) was significantly increased after CORT action. These results suggest that CORT can inhibit the proliferation of cardiac myocytes and promote apoptosis, stimulate cells to change to the hypertrophic phenotype and cause abnormal cardiac hypertrophy. The contractile function is reduced. Based on the active metabolism of the heart, the high energy demand and the abundant mitochondria, the development of a series of heart diseases is closely related to the abnormal mitochondrial metabolic function. The related research shows that the dysfunction of mitochondria is considered to be the main factor to promote the changes of myocardial pathology and to the heart failure. The effect of CORT on mitochondrial function in the myocardium of chicken embryo was further studied. After CORT (2.5 and 5nmol) were injected into the edd3 chicken embryo gas chamber every other day, the heart tissue of chicken embryo was incubated in edd14, the mitochondrial cell line was extracted by the mitochondrial separation kit, and the mitochondrial membrane potential was detected by flow cytometry. M and the real-time monitoring of the formation rate of ROS in mitochondria through a fluorescent enzyme labeling instrument. The change of energy substance ATP content in the hypertrophic myocardium was measured by HPLC method. In addition, the activity of mitochondrial respiratory chain complex was determined by the reagent box, and the activity of mitochondrial respiratory chain complex was determined respectively. The results showed that the CORT load could affect the chicken significantly. The mitochondrial function of embryonic cardiac myocytes is characterized by a decrease in M, an increase in the rate of ROS production, a significant decrease in the content of ATP, the increase in the MDA content of the lipid peroxidation product and a significant decrease in the relative amount of the antioxidant enzyme MnSOD activity and the antioxidant molecule gsh/gssg. Meanwhile, the CORT load will also lead to the activity of mitochondrial respiratory chain complex in the chicken embryo cardiac myocytes. III, IV, V decreased significantly. In addition, through transmission electron microscopy, we also observed that after the injection of CORT, the mitochondria in the cardiac myocytes were clustered and presented clusters of abnormal phenomena. The results suggested that the CORT load could lead to the abnormal mitochondrial morphology and function in the chicken embryo cardiac myocytes. The mitochondrial fusion protein 2 (mitofusin2, Mfn2) protein is a mediating wire. An important protein of granular fusion is involved in maintaining mitochondrial dynamic balance and structural homeostasis. In the recent study in the rodent stress model, stress induced hormone CORT can affect the mitochondrial structure and function of the brain by regulating Mfn2 expression. Therefore, we suspect that the CORT load leads to the disorder of the embryonic heart development and is associated with the disorder of the embryonic heart. The dysfunction of mitochondrial dysfunction involved the abnormal expression of Mfn2. The expression of Mfn2 protein in the myocardium of chicken embryo was detected by westernblotting. The results showed that the expression level of Mfn2 protein in the myocardium of chicken embryo of CORT load group was significantly higher than that of the control group. In order to further verify that CORT induced cardiomyocyte hypertrophy was indeed a line granule mediated by Mfn2. In this study, CORT (200 m, 48h) was used to establish an in vitro model of H9c2 in rat embryonic cardiomyocytes. The experiment was divided into three groups: control, CORT and cort+gr antagonist (RU486). The effect of CORT on the morphology of H9c2 cells, the level of Mfn2 protein and the change of the mitochondrial membrane potential were observed, and the cell water was detected by westernblotting. The expression of flat apoptotic related proteins. Finally, the effects of Mfn2 protein on the structure and apoptosis of cardiac myocytes were detected. The results showed that the abnormal development of cardiac hypertrophy induced by CORT was realized by regulating Mfn2. The results showed that after the action of CORT, the H9c2 cells had the same result as the chicken embryo experiment, CORT It can increase the volume of cardiac myocytes, increase the expression of Mfn2 protein, decrease the mitochondrial membrane potential m and increase the relative level of Bcl-2 protein family Bax/Bcl-2, increase the apoptosis of cardiac myocytes. The changes of the previous changes can be improved accordingly on the basis of GR antagonist (Ru486,10 mu M) in advance, suggesting that CORT may pass through. GR mediated the changes in the structure and apoptosis of the cardiomyocytes. At the same time, after transfection of Mfn2, the apoptotic protein Bax/Bcl-2 increased significantly, the expression of activated Caspase3 protein increased and the mRNA level of cardiac hypertrophy gene SKA increased. It indicated that CORT could damage mitochondria and promote apoptosis by regulating Mfn2 expression, resulting in ventricular wall. The decrease in number of cells leads to cardiac damage and hypertrophy. To sum up, CORT can induce myocardial mitochondrial dysfunction by regulating Mfn2, leading to abnormal cardiac energy metabolism, excessive ROS production and promoting cardiac cell apoptosis, and eventually leading to abnormal hypertrophy of heart development, which provides new therapeutic targets for prevention and control of such related heart diseases. Point and theoretical basis.
【學(xué)位授予單位】：暨南大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R965

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