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研究生:詹馥綺
研究生(外文):Fu-Chi Chan
論文名稱:心基因缺陷小鼠左心房-肺靜脈心肌細胞電生理學特性
論文名稱(外文):Electrophysiological characteristics of the left atrium-pulmonary vein cardiomyocytes obtained from Xinα-deficient mouse heart
指導教授:林正一林正一引用關係
指導教授(外文):Cheng-I Lin
學位類別:碩士
校院名稱:國防醫學院
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:65
中文關鍵詞:心基因左心房-肺靜脈小鼠
外文關鍵詞:Xin geneleft atrium-pulmonary veinmice
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前言:
心臟動作電位的發生和傳導與離子通道的活性、細胞與細胞間的傳導和心臟組織的結構有著複雜的關聯。近年來學者研究指出,Xin是一個Nkx2.5轉錄因子的下游基因,可能參與對心臟發育相當重要的BMP-Nkx2.5-MEF2C途徑。利用雙標記免疫螢光染色法 (double-label immunofluorescent),發現Xin蛋白在胚胎時期即與β-catenin、N-cadherin有90%的重疊,在成鼠心臟介間盤的部分,Xin蛋白亦和connexin-43有80%重疊,顯示Xin蛋白表現於介間盤 (intercalated disc) 的adheren junction,在gap junction也可能有表現。因此心基因不僅對於心臟分化發育相當重要,對於心肌細胞間的連結、衝動傳導以及細胞骨架間的整合也扮演關鍵角色。因此心基因缺陷,可能造成介間盤結構缺損或是細胞間傳導障礙,相關研究亦顯示心基因缺陷小鼠會產生心肌肥大的現象。

實驗目的:
比較野生型小鼠 (wild-type mice) 與心基因缺陷小鼠 (mXinα-deficient mice;mXinα+/- and mXinα-/-) 之左心房-肺靜脈心肌細胞動作電位、各離子電流特性以及細胞內鈣離子濃度變化。

實驗方法:
一、Xin基因型小鼠的鑑定
取小鼠尾巴做聚合酵素連鎖反應 (Polymerase Chain Reaction, PCR),以確定實驗用的每隻小鼠之基因型態。

二、 小鼠左心房-肺靜脈心肌細胞之分離
1. 將15-25週小鼠 (體重為25-35公克) 以sodium pentobarbital (50 mg/Kg i.p.) 麻醉,經胸腔部開術取出完整的心臟與肺臟置於HEPES-Tyrode溶液中。
2. 以絲線將主動脈口固定於0.35 mm PE管的一端,另一端則與Langendorff灌流柱接合,以37℃ 100% 氧氣飽和灌流液進行冠狀動脈逆行性灌流,將心臟內之血液灌洗出,直至血液完全排出。
3. 以Ca2+-free HEPES-Tyrode溶液灌洗5分鐘,目的使心臟不再跳動、組織完全鬆弛。
4. 以Ca2+-free HEPES-Tyrode溶液含有collagenase (1 mg/ml) 及protease (0.01 mg/ml) 等兩酵素進行酵素溶液灌流,灌流約9-15分鐘不等。
5. 最後以Ca2+-free HEPES-Tyrode溶液灌洗15分鐘,減少酵素作用。分離出單一細胞後,逐次以HEPES-Tyrode溶液將Ca2+-free HEPES-Tyrode溶液更換掉,將鈣離子濃度回昇至生理常態濃度。
三、單一左心房-肺靜脈心肌細胞之電生理研究
本實驗採whole-cell patch-clamp技術,以電位箝定方式觀察三種型態小鼠之左心房-肺靜脈心肌細胞各離子電流的變化;及電流箝定方式觀察動作電位之異同。

四、共軛焦螢光顯微鏡技術
將分離出來的左心房-肺靜脈心肌細胞加入Fluo-3-Am 鈣離子螢光染劑,再使用共軛焦螢光顯微鏡來觀察三種型態小鼠之左心房-肺靜脈心肌細胞內鈣離子濃度變化。

五、實驗數據分析
利用unpair t test、One-way ANOVA以及卡方檢定 (Chi-square) 進行數據分析。

實驗結果:
一、以實驗中記錄到的細胞電容,比較心基因缺陷小鼠與野生型小鼠左心房-肺靜脈心肌細胞大小差異,結果野生型小鼠、心基因缺陷小鼠異質體及同質體細之胞電容依序為36.7±1.5 pF、41.9±1.7 pF、50.5±3.4 pF,其間三組兩兩比較,均達統計顯著差異。表此時期心基因缺陷小鼠之左心房-肺靜脈心肌細胞有肥大的情形。

二、在電流箝定模式下1Hz的電刺激誘發動作電位。三組間比較,心基因缺陷小鼠再極化20%、50%、90%的動作電位期間 (APD20、APD50、APD90) 與野生型小鼠比較皆有顯著延長。APD20:依序為6.6±0.6 ms、7.4±1.0 ms及8.9±0.9 ms;APD50:依序為16.3±1.5 ms、18.1±2.8 ms及 23.6±2.1 ms;APD90:依序為46.3±3.7 ms、48.8±11.8 ms及75.0±7.2 ms。
三、三組在電流箝定模式下,1 Hz的電刺激下皆可記碌到DAD (delayed afterdepolarization),但未達統計差異。
四、電位箝定下,與野生型小鼠比較,發現心基因缺陷小鼠INa、Ito、IK及ICa,L之電流密度均較小,且達統計顯著差異。而IK1無統計差異。
五、使用共軛焦螢光顯微鏡技術發現,在2 Hz刺激下,心基因缺陷小鼠細胞內鈣離子濃度顯著較野生型低,且鈣離子衰退時間也顯著較短。

結論:
心基因缺陷小鼠的左心房-肺靜脈心肌細胞顯著較野生型小鼠大,但細胞內鈣離子濃度卻顯著較少。而肥大的心基因缺陷小鼠心肌細胞,其鈉離子電流 (INa)、鉀離子電流 (Ito、IK) 和L型鈣離子電流 (ICa,L) 皆顯著較野生型小,因此導致較長的動作電位期間。
Introduction
Xin, one of the downstream targets of the Nkx2.5 and MEF2C transcription factors, is a striated muscle-specific gene. Xin protein localizes to the adherens junctions and gap junctions of the intercalated discs. It may play important roles in cardiac morphogenesis, formation and maintenance of the intercalated disc and myofibril integrity. Xin may also participate in generation and propagation of cardiac action potential. Xin expression is significantly up-regulated in pressure-overload animals and deficiency of Xin may lead to spontaneous hypertrophy in the hearts.

Aim
The aims of the present study were to compare the electrophysiological features and calcium homeostasis in the left atrium-pulmonary vein (LA-PV) myocytes of wild-type and mXinα-deficient mouse.

Material and Methods
a. Gene typing
Xin gene typing was determined by polymerase chain rection (PCR).
b. Isolation of LA-PV myocytes
Male mice (C57BL/6J, 25-35 gm) and age-matched male Xinα-deficient mice (15-25 weeks old) were anesthetized with sodium pentobarbital (50mg/Kg i.p.) and the heart and lungs quickly removed and immersed in HEPES-Tyrode solution. The LA-PV were perfused in a retrograde manner via polyethylene tube connected through the aorta and left ventricular into the left atrium. The free end of the polyethylene tubing was connected to a langendorff perfusion column for perfusion with HEPES-Tyrode solution at 37℃. The perfusion was replaced with oxygenated Ca2+-free HEPES-Tyrode solution, then was replaced with containing collagenase (1 mg/ml) and protease (0.01 mg/ml) finally. Afterwards the LA-PV were cut away from the ventricle and lung and placed in a dissection chamber containing Ca2+-free HEPES-Tyrode solution. The piece of tissue was cut into fine pieces and shaken in 5 ml of oxygenated Ca2+-free HEPES-Tyrode solution until single LA-PV myocytes obtained.

c. Electrophysiological study
The isolated cells were placed in a chamber mounted on the stage of an inverted microscope and superfused with extracellular solution appropriate to each patch-clamp experiment. Only cells showing clear cross striations were used for experiment on following ion currents and membrane potentials by means of whole-cell patch-clamp technique (action potentials were recored in current-clamp mode and voltage-gated ionic currents in voltage-clamp mode):action potentials (AP), sodium current (INa), transient outward potassium current (Ito), delay rectifier potassium current (IK), L-type calcium current (ICa,L) and inward rectifier potassium current (IK1).

d. Confocal microscopy technique
LA-PV cardiomyocytes were loaded with a fluorescent Ca2+ (10 μM) fluo-3/AM. The Ca2+ transient, and decay portion of the Ca2+ transient were measured during a 2 Hz field-stimulation.

Result
1. Sarcolemmal capacitance of wild-type and mXinα-deficient (mXinα+/- and mXinα-/-) cardiomyocytes were determined by a small hyperpolarizing step from -50 to -55 mV for 80 ms. Our results show that the mXinα+/- and mXinα-/- myocytes have a larger membrane capacitance than the wild-type myocytes. The action potential duration at 20%, 50% and 90% repolarization level (APD20, APD50 and APD90) were significantly longer in mXinα-/- as compared to wild-type cardiomyocytes.

2. Na+ current, transient outward K+ current (Ito) and delayed rectified K+ current (IK) were significantly reduced in mXinα-/- as compared to wild-type. Also peak L-type Ca2+ current (ICa,L) was decreased in mXinα-/-. But no significant difference in Ba2+-sensitive inward rectifier K+ current (IK1) between mXinα-/- and wild-type.

3. Amplitude of [Ca2+]i (F/F0) was significantly reduced in mXinα-/- as compared to wild-type and the time constant (τ) for the decay of Ca2+ transient was smaller in mXinα-/-.

Conclusion
It is concluded that mXinα-/- cardiomyocytes are larger than the wild-type myocytes in size but contain less intracellular Ca2+. The hypertrophied mXinα-/- myocytes have a longer APD associated with a simultaneous reduction of Na+, K+ and Ca2+ currents.
目錄
頁次
目錄------------------------------------------------------------------------------- I
圖目錄---------------------------------------------------------------------------- IV
表目錄---------------------------------------------------------------------------- V
中文摘要------------------------------------------------------------------------- VI
英文摘要------------------------------------------------------------------------- X
第一章 緒言------------------------------------------------------------------ 1
第一節 心臟的發育------------------------------------------------------ 1
第二節 心基因簡介------------------------------------------------------ 1
第三節 介間盤------------------------------------------------------------ 6
第四節 左心房-肺靜脈的介紹----------------------------------------- 8
第五節 動作電位相關的離子流簡介--------------------------------- 9
第二章 研究目的------------------------------------------------------------ 15
第三章 材料與方法--------------------------------------------------------- 16
第一節 實驗動物--------------------------------------------------------- 16
第二節 小鼠左心房-肺靜脈心肌細胞之分離----------------------- 16
第三節 玻璃微電極與實驗裝置--------------------------------------- 18
第四節 全細胞膜電位箝定--------------------------------------------- 18
第五節 電生理實驗方法------------------------------------------------ 20
第六節 共軛焦螢光顯微鏡技術--------------------------------------- 22
第七節 實驗藥物及溶液------------------------------------------------ 24
第八節 鑑定小鼠的Xin基因型---------------------------------------- 25
第九節 實驗數據與統計------------------------------------------------ 29
第四章 實驗結果------------------------------------------------------------- 31
第一節 鑑定小鼠的Xin基因型---------------------------------------- 31
第二節 野生型小鼠與心基因缺陷小鼠之左心房-肺靜脈心肌細胞動作電位比較---------------------------------------------

31
第三節 野生型小鼠與心基因缺陷小鼠之左心房-肺靜脈心肌細胞各離子電流比較------------------------------------------

33
第四節 野生型小鼠與心基因缺陷小鼠之左心房-肺靜脈心肌細胞內鈣離子濃度比較---------------------------------------

35
第五章 討論------------------------------------------------------------------- 46
第一節 心基因缺陷導致心肌肥大之探討--------------------------- 46
第二節 心基因缺陷與野生型小鼠動作電位之探討--------------- 47
第三節 心基因缺陷與野生型小鼠鈉離子電流之探討------------ 49
第四節 心基因缺陷與野生型小鼠鉀離子電流之探討------------ 50
第五節 心基因缺陷與野生型小鼠L型鈣離子電流之探討------ 51
第六節 心基因缺陷與野生型小鼠細胞內鈣離子濃度探討------ 52
第六章 結論------------------------------------------------------------------ 54
第七章 參考文獻------------------------------------------------------------- 55

圖目錄
頁次
圖1-1 心臟發育之側面板狀中胚層分化圖------------------------------ 13
圖1-2 心臟發育及其相關的基因流程示意圖--------------------------- 14
圖3-1 傳統光學顯微鏡與共軛焦顯微鏡之比較------------------------ 30
圖4-1 鑑定Xin基因型小鼠聚合酵素連鎖反應圖---------------------- 36
圖4-2 電刺激下,小鼠心肌細胞典型動作電位圖--------------------- 38
圖4-3 電刺激下,小鼠心肌細胞記錄到的DAD圖------------------- 39
圖4-4 小鼠心肌細胞鈉離子流之比較圖--------------------------------- 40
圖4-5 小鼠心肌細胞短暫外向鉀離子流之比較圖--------------------- 41
圖4-6 小鼠心肌細胞延遲整流型鉀離子流之比較圖------------------ 42
圖4-7 小鼠心肌細胞鋇敏感性內向整流型鉀離子流之比較圖------ 43
圖4-8 小鼠心肌細胞L型鈣離子流之比較圖--------------------------- 44
圖4-9 小鼠心肌細胞內鈣離子濃度變化之比較圖--------------------- 45

表目錄
頁次
表一 小鼠之心肌細胞動作電位參數比較------------------------------- 37
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