本文選題：心房纖顫 + 鈣調(diào)神經(jīng)磷酸酶�。� 參考：《山東大學(xué)》2017年碩士論文

【摘要】：研究背景隨著我國人口結(jié)構(gòu)老齡化,心房纖顫(atrial fibrillation,AF)的發(fā)生率逐漸提高。瓣膜性心臟病伴發(fā)房顫時,栓塞和心衰的風險成倍增加,成為家庭和社會巨大的醫(yī)療負擔。目前關(guān)于房顫的發(fā)生有很多假說,比如心肌結(jié)構(gòu)重塑,局灶沖動連續(xù)發(fā)放,多發(fā)折返環(huán),以及離子通道電流失常等等。但是,準確的發(fā)病機制仍未完全清楚。近年來,鈣調(diào)神經(jīng)磷酸酶(Calcineurin,CaN)因在心肌肥厚中發(fā)揮重要作用備受關(guān)注。CaN是一種Ca2+/鈣調(diào)蛋白依賴的蛋白磷酸酶,可將細胞漿中的活化T細胞核因子(Nuclear Factor of Activated T-cells,NFAT)去磷酸化從而使其激活,活化的NFAT轉(zhuǎn)入細胞核,啟動心肌肥厚基因的表達。與此作用相反的是,糖原合成激酶3β(glycogen synthase kinase 3β,GSK3β)又可將NFAT磷酸化使其失活,促進NFAT轉(zhuǎn)出細胞核,中斷肥厚基因表達。蛋白激酶B(Protein kinase B,Akt/PKB)是GSK3β上游一個強有力的調(diào)節(jié)因子,當Akt第473位絲氨酸(Ser-473)被磷酸化,轉(zhuǎn)變成活化形式p-Akt,p-Akt可將GSK3β位于N端的第9位絲氨酸(Ser-9)磷酸化,使其轉(zhuǎn)變成無活性的p-GSK3β。最近,有研究表明CaN-NFAT通路參與了房顫的發(fā)生。基于CaN-NFAT通路和GSK3β-NFAT通路在心肌肥厚過程中的交叉關(guān)系,我們推測直接影響NFAT活性的Akt-GSK3β通路也可能參與了房顫的發(fā)生過程。然而,關(guān)于瓣膜性房顫中Akt-GSK3β信號通路的研究數(shù)據(jù)有限,尤其是人類中更少。因此,設(shè)計這個實驗用來探究Akt-GSK3β信號通路是否參與人類瓣膜性房顫的發(fā)生。研究目的探討Akt-GSK3β信號通路與瓣膜性房顫發(fā)生的關(guān)系。研究方法研究對象包括42名接受心臟換瓣手術(shù)的成人瓣膜病患者,按患者的心律狀況分為2組:心房纖顫組(n=18),竇性心律組(n=24),手術(shù)前收集患者的一般資料及輔助檢查的數(shù)據(jù)。通過蛋白免疫印跡法檢測患者左心房心肌組織中鈣調(diào)神經(jīng)磷酸酶(CaN),總蛋白激酶B(total Akt),磷酸化蛋白激酶B(p-Akt),總糖原合成激酶3β(total GSK3β)和磷酸化糖原合成激酶3β(p-GSK3β)的蛋白表達水平,以磷酸甘油醛脫氫酶(GAPDH)為內(nèi)參,所得條帶灰度值的比值作為以上蛋白表達的相對含量。研究結(jié)果1.臨床特征方面的分析:兩組病人在性別、年齡、血壓、BMI等方面,未見統(tǒng)計學(xué)差異(P均0.05);但房顫組病人的心率、BNP明顯高于竇律組,其差異具有統(tǒng)計學(xué)意義(P均0.05)。2.服用藥物方面的分析:房顫組病人服用β阻劑和地高辛的比率高于竇律組,其差異具有統(tǒng)計學(xué)意義(P均0.05);其他藥物方面未見統(tǒng)計學(xué)差異(P均0.05)。3.心功能方面的分析:房顫組病人的心功能較竇律組差,具體表現(xiàn)在左心室射血分數(shù)偏低,其差異具有統(tǒng)計學(xué)意義(P0.05)。4.兩組樣本中Akt-GSK3β及CaN蛋白表達情況分析:以GAPDH為參照,房顫組活化形式的p-Akt、非活化形式的p-GSK3β及總GSK3β蛋白表達水平均高于竇性心律組(p-Akt 1.027±0.126 vs 0.729±0.113,P0.001;p-GSK3β0.802±0.116 vs 0.482±0.076,P0.001;total GSK3β 1.047±0.162 vs 0.703±0.109,P0.001),其差異具有統(tǒng)計學(xué)意義,提示房顫心房肌活化形式的p-Akt蛋白表達增加,使GSK3β變成失活形式的p-GSK3β增加,從而使NFAT從細胞核轉(zhuǎn)出核外的作用減弱,促進了房顫的發(fā)生。此外,兩組樣本之間總Akt(1.074±0.089 vs 1.028±0.0945,P=0.124)的蛋白表達水平未見統(tǒng)計學(xué)差異。房顫組中CaN(1.097±0.153 vs 0.919±0.142,P0.001)的蛋白表達水平高于竇律組。研究結(jié)論蛋白激酶B-糖原合成激酶3β信號通路參與了瓣膜性房顫的發(fā)生。
[Abstract]:Background: the incidence of atrial fibrillation (AF) is increasing with the aging of the population structure in our country. The risk of embolism and heart failure is multiplied times when valvular heart disease is associated with atrial fibrillation. There are many hypotheses about the occurrence of atrial fibrillation, such as the remodeling of myocardial structure, and the focal impact. Continuous distribution, multiple reentry rings, and ion channel current aberration and so on. But the exact pathogenesis is still not completely clear. In recent years, Calcineurin (CaN) plays an important role in cardiac hypertrophy. It is concerned that.CaN is a Ca2+/ calmodulin dependent protein phosphatase, which can activate T in the cytoplasm. Nuclear Factor of Activated T-cells (NFAT) is dephosphorylated to activate it, and the activated NFAT is transferred into the nucleus and activates the expression of the hypertrophic gene of the myocardium. In contrast, the glycogen synthesis kinase 3 beta (glycogen synthase kinase 3 beta, GSK3 beta) can also phosphorylate the NFAT, and promote the transfer of the nucleus to the nucleus. Protein kinase B (Protein kinase B, Akt/PKB) is a powerful regulator in the upstream of GSK3 beta. When Akt 473rd serine (Ser-473) is phosphorylated and transformed into active form p-Akt, p-Akt can phosphorylate the ninth bit serine of GSK3 beta at the N end and turn it into an inactive beta. Recently, a study table The CaN-NFAT pathway is involved in the occurrence of atrial fibrillation. Based on the cross relationship between the CaN-NFAT pathway and the GSK3 beta -NFAT pathway in the process of myocardial hypertrophy, we speculate that the Akt-GSK3 beta pathway that directly affects the NFAT activity may also be involved in the process of atrial fibrillation. However, the data on the Akt-GSK3 beta signaling pathway in valvular atrial fibrillation is limited, especially in the case of valvular atrial fibrillation. This experiment is designed to explore whether the Akt-GSK3 beta signaling pathway is involved in valvular atrial fibrillation. The purpose of this study is to explore the relationship between the Akt-GSK3 beta signaling pathway and valvular atrial fibrillation. The research object included 42 adult valvular patients who underwent cardiac valve replacement surgery, according to the heart rhythm of the patients. The conditions were divided into 2 groups: the atrial fibrillation group (n=18), the sinus rhythm group (n=24), the general data of the patients before the operation and the data of the auxiliary examination. The protein immunoblotting was used to detect the calcineurin (CaN), the total protein kinase B (total Akt), the phosphorylated protein kinase B (p-Akt), the total glycogen kinase 3 beta (total G) in the left atrial myocardium of the patients. SK3 beta and phosphorylated glycogen synthesis kinase 3 beta (p-GSK3 beta) protein expression level, glyceraldehyde phosphate dehydrogenase (GAPDH) as the internal parameter, the ratio of gray value of the bands as the relative content of the above protein expression. Study results 1. clinical characteristics of the analysis: two groups of patients in sex, age, blood pressure, BMI and so on, no statistical difference (P All 0.05), but the heart rate of the patients with atrial fibrillation was significantly higher than that in the sinus rhythm group, and the difference was statistically significant (P 0.05).2. medication analysis: the ratio of beta blockers and digoxin in the atrial fibrillation group was higher than that in the sinus rhythm group, and the difference was statistically significant (P 0.05), and there was no statistical difference between other drugs (P 0.05).3. cardiac work Analysis of energy: the heart function of the patients with atrial fibrillation is worse than that in the sinus rhythm group, and the specific expression is that the left ventricular ejection fraction is low. The difference is statistically significant (P0.05) the expression of Akt-GSK3 beta and CaN in the samples of.4. two groups: GAPDH as the reference, the activation of p-Akt in the atrial fibrillation group, the expression of the non activated p-GSK3 beta and the total GSK3 beta protein expression The levels were higher than that in the sinus rhythm group (p-Akt 1.027 + 0.126 vs 0.729 + 0.113, P0.001, p-GSK3 beta 0.802 + 0.116 vs 0.482 + 0.076, P0.001, total GSK3 beta 1.047 + 0.162 vs 0.703 + 0.109, P0.001), and the difference was statistically significant, suggesting that the expression of p-Akt protein in atrial fibrillation of atrial fibrillation increased. In addition, the role of NFAT from the nucleus out of the nucleus weakened and promoted the occurrence of atrial fibrillation. In addition, the protein expression level of total Akt (1.074 + 0.089 vs 1.028 + 0.0945, P=0.124) between the two groups was not statistically significant. The protein expression level of CaN (1.097 + 0.153 vs 0.919 + 0.142, P0.001) in the atrial fibrillation group was higher than that in the sinus rhythm group. The white kinase B- glycogen synthase kinase 3 beta signaling pathway is involved in valvular atrial fibrillation.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R541.75

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