臺灣博碩士論文加值系統

前言
1999 年美國愛荷華大學林敬清教授於雞胚胎期，利用原位雜交法(whole mount in situ hybridization)發現Xin 基因，並在雞胚胎第6 期給予Xin antisense oligonucleotides 能阻斷Xin 基因的表現，造成心臟發育異常。Xin 基因在小鼠有mXinα (甲型)及mXinβ (乙型)兩型，生成蛋白主要位於Intercalated disk (ICD)中，在甲型心基因剔除小鼠發現有心臟肥大、動作電
位延長以及傳導變慢的現象，但無出生後致死的現象；然而又在甲型心基因剔除小鼠研究中，發現mXinβ 蛋白質表現量增加，故認為mXinβ 具有代償 mXinα 之角色。在乙型同質型心基因剔除小鼠研究中，發現有不正常的心臟形狀、心室中膈缺損、生長遲緩及離乳前(約18 天)的高死亡率；並無發現mXinα表現量增加來代償之情形，所以認為mXinβ 比 mXinα 在心臟發育及心臟分化中具有更重要的角色。臨床上最常見的心律不整為心房纖維顫動，有研究指出左心房是產生心房纖維顫動很重要的區域。藉由以上因素促使我
們想要探討mXinβ 基因剔除小鼠左心房電生理特性。

目的
本研究目的主要要探討mXinβ 基因剔除小鼠左心房心肌組織電生理的特性，並觀察左心房心律不整的發生率。

實驗動物
本實驗以野生型小鼠(wild–type, 5-10 天) 做為實驗之對照組；及乙型同質型基因剔除小鼠(Xinβ-/-, 5-10 天) 做為實驗之實驗組進行電生理研究。

實驗方法
一、 Xin 基因小鼠的鑑定
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、 高速光譜影像技術(optical mapping)
利用此電生理系統，記錄乙型同質型心基因剔除小鼠左心房心肌組織的傳導速度變化。
三、 傳統玻璃微電極技術及收縮張力轉換器
利用微電極技術探討乙型同質型心基因剔除小鼠左心房的動作電位變化，而張力轉換器記錄組織收縮力。給予離子通道抑制劑比較乙型心基因剔除小鼠及野生型小鼠離子通道之差異。抑制劑如下：超快速延遲整流型電流(ultrarapid delayed rectifier current；IKur) 及短暫向外鉀離子流(transient outward potassium current；Ito) 抑制劑：4-aminopyridine
50 μM 及1000 μM。L 型鈣離子流抑制劑：nicardipine 3 μM。鈉離子流抑制劑：lidocaine 3 μM、30 μM 及300 μM。β−接受器的致效劑：isoproterenol 1 μM。
四、 西方墨點法
利用西方墨點法技術測量Cx40、Nav1.5、Kv1.5、Kv4.2、Cav1.2、SERCA及RYR 的蛋白質表現量。
五、 實驗數據分析
利用 unpaired t-test、paired t-test 以及卡方檢定(Chi-square)進行數據分析。

實驗結果
1. 實驗結果顯示，年齡匹配的乙型同質型心基因剔除小鼠的體重(BW)較野生型小鼠輕，且有統計上差異，而心重(HW)和野生型小鼠無
差異。因體重過輕，故乙型同質型心基因剔除小鼠的心重與體重之比值(HW/BW)比野生型小鼠重，有統計差異。
2. 利用電生理光學影像系統，記錄乙型同質型心基因剔除小鼠之左心房組織的傳導速度較野生型小鼠慢，而乙型異質型基因剔除小鼠
(Xinβ+/-,5-10 天)和野生型小鼠相比無差異。
3. 利用傳統微電生理技術，給予4Hz 電刺激，記錄乙型同質型心基因剔除小鼠之左心房動作電位期間顯著較野生型小鼠縮短。利用加
入離子通道抑制劑方式，測Ito、ICa,L 及INa 通道，發現乙型同質型心基因剔除小鼠的Ito 相較於野生型小鼠增加，而ICa,L、
INa 相較於野生型小鼠減少，而Ikur 則沒有顯著差異。
4. 利用西方墨點法，測量乙型同質型心基因剔除小鼠的Kv4.2 蛋白質表現量較野生型小鼠多，Cav1.2、Cx40 及Nav1.5 的蛋白質表
現量較低，而Kv1.5 及SERCA 蛋白質的表現量，無顯著性差異。
5. 記錄乙型同質型心基因剔除小鼠和野生型小鼠出現早發性後去極化（early after-depolarization；EAD）、激發性活性(
triggered rhythms )和自發性活性( automatic rhythms )的頻率無顯著性差異。在1000 μM 4-AP washout 30 分鐘內，
野生型小鼠左心房心肌組織出現自發性節律的次數比乙型同質型心基因剔除小鼠高，而在isoproterenol 作用下，
野生型小鼠左心房心肌組織出現激發性節律的次數比乙型同質型心基因剔除小鼠高。

結論：
乙型同質型心基因剔除小鼠之左心房動作電位期間顯著較野生型小鼠縮短，主要是因為同質型心基因剔除小鼠左心房的Kv4.2 蛋白質表現量較多，而Cav1.2 及Nav1.5 的蛋白質表現量較低，使得Ito 相較於野生型小鼠增加，而ICa,L、INa 相較於野生型小鼠減少。我們發現野生型小鼠及同質型心基因剔除小鼠心律不整的發生率沒有統計差異，然而實驗中給予4-AP 以及isoproterenol 作用下，自發性節律及激發性節律的發生率，同質型心基因剔除小鼠相較於野生型小鼠是比較低的，可能與乙型心基因剔除小鼠的傳導速度變慢且電性產生改變有關。

Introduction
The Xin repeat– containing proteins from chicken and mouse hearts (cXin and mXinα, respectively) were first identified as a target of the Nkx2.5-Mef2C pathway. Another mouse Xin protein, mXinβ (or
myomaxin), has been subsequently identified as a Mef2A downstream target. Xin is localized at intercalated discs implicated in cardiac morphogenesis. Loss of mXinα, results in cardiac hypertrophy and cardiomyopathy with conduction defects. In the mXinα-deficient mice, mXinβ protein is up-regulated protein levels, suggesting a compensatory role of mXinβ. Ablation of mXinβhas been shown to lead
to abnormal heart shape, ventricular septal defects and postnatal lethality. mXinβ may play an essential role in heart morphogenesis,formation and maintenance of the intercalated disc and myofibril
integrity, and in generation and propagation of cardiac action potential.Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia.Previous studies have shown that the left atrium (LA) is important in the AF pathyphysiology. This observation prompts us to further investigate the electrophysiological characteristics of left atrium obtained from neonatal Xinβ-null mouse heart.

Aim
We investigate the electrophysiological characteristics of left atrium obtained from neonatal Xinβ-null mouse heart.

Meterial and Methods
(1)Gene typing
PCR (polymerase chain reaction) was used to confirm genomic type of Xinβ-null mice.
(2)Optical mapping
Extra-cellular recordings of cardiac electrical activities and conduction velocity (CV) were
determined with a optical mapping on left atrium tissues driven at 6Hz.
(3)Microelectrode techniques and transducer
Action potentials were recorded by microelectrode techniques and twitch force by a transducer. The
remaining LA were driven at 4Hz.
(4)Drug
4-aminopyridine: Ito and IKur blocker, nicardipine: ICa blocker.lidocaine: INa blocker.
Isoproterenol:β- receptor agonist.
(5)Western blotting
We examined the Cx40, Nav1.5, Kv1.5, Kv4.2, Cav1.2, SERCA,RyR protein expression levels by Western
blotting.

Results
1. The body weight (BW) of mXinβ-/- mice was lighter than wild-type(WT). The heart weights (HW) of WT
and mXinβ-/- mice were no difference. The HW/BW ratio of mXinβ-/- mice was significantly higher than
WT mice.
2. The results show CV of mXinβ-/-mice were significantly slower than WT mice.
3. The maximum rate of rise in the upstroke of action potential was significantly decreased in the
mXinβ-/- mice.
4. The duration of the action potential at 20%, 50% and 90% of repolarization (APD20, APD50 and APD90,
respectively) in mXinβ-/- mice LA were significantly shorter than WT mice.
5. After addition of 50 μM 4-aminopyridine (4-AP), which blocks IKur, dramatically lengthened all
levels of APD in both groups, suggesting that there was no difference between mXinβ-/- mice and WT
mice.
6. Addition of 1mM 4-AP, which blocks Ito, significantly prolonged the APDs in two groups, but
percentage of prolonged APD20 in mXinβ-/- mice (68+13%) was significantly larger than in WT mice.
(35+8 %), suggesting that Ito in mXinβ-/- mice could stronger than WT.
7. A Ca2+ channel blocker, nicardipine, significantly shortened the APD of WT, but failed to shorten
that of mXinβ-/- mice, suggest that the ICa,L in mXinβ-/- mice is very small.
8. A late Na+ channel blocker, lidocaine, significantly shortened the APD of WT, but failed to shorten
that of mXinβ-/- mice, suggest that the INa, Late in mXinβ-/- mice is very small.
9. The expression level of Kv4.2 protein was significantly higher than WT mice. The levels of Cav1.2,
Nav1.5, Cx40 and RYR protein were significantly decreased in mXinβ-/- mice. The levels of Kv1.5 and
SERCA were no difference between two groups.
10.On the other hand, during washout of 1mM 4-AP, we found a higher incidence of automatic rhythms in
WT mice.
11. Addition 1μM isoproterenol, we found to lower the incidence of triggered rhythms in mXinβ-/- mice .

Conclusion
We found the mXinβ-/- mice protein expression levels of Cav1.2 and Nav1.5 were decreased, and the expression level of Kv4.2 protein was increased, that results in reduced L-type Ca2+ and Na+ channel
and increased transient outward potassium. These results explain why left atrium tissues from 5~10 day-old mXinβ-/-mice have shorter action potential duration. On the other hand, we found a higher incidence of automatic and triggered rhythms in WT. Interesting, the mXinβ-/- mice may induce remodeling of electrical activity and slower CV, which lead to lower incidence of atrial arrhythmias during washout of 4-AP and exposure isoproterenol.

目錄
頁次
目錄 -------------------------------------------------------------------------------------I
圖目錄-------------------------------------------------------------------------------- IV
表目錄-------------------------------------------------------------------------------- VI
中文摘要---------------------------------------------------------------------------- VII
英文摘要----------------------------------------------------------------------------- XI
第一章 緒論-------------------------------------------------------------------------- 1
第一節心基因的起源- ---------------------------------------------------------- 1
第二節心基因的序列結構----------------------------------------------------- 2
第三節心基因在心臟發育中可能扮演的角色----------------------------- 3
第四節心基因在心臟介間盤中扮演的角色-------------------------------- 6
第五節介間盤-------------------------------------------------------------------- 7
第六節心基因相關的研究----------------------------------------------------- 9
第七節心房纖維顫動---------------------------------------------------------- 11
第八節心律不整---------------------------------------------------------------- 12
第九節動作電位相關的通道蛋白質簡介---------------------------------- 15
第二章 研究目的------------------------------------------------------------------- 17
第三章 材料與方法---------------------------------------------------------------- 18
II
第一節 實驗動物----------------------------------------------------------------- 18
第二節 鑑定小鼠的Xin 基因-------------------------------------------------- 18
第三節 高速光譜影像技術 (Optical Mapping System)----------------- 21
第四節 左心房動作電位和收縮張力記錄----------------------------------- 22
第五節 蛋白質萃取-------------------------------------------------------------- 23
第六節 蛋白質膠體電泳分析-------------------------------------------------- 25
第七節 西方墨點法(Western blot) ---------------------------------------- 27
第八節 實驗溶液及藥物-------------------------------------------------------- 28
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Xinβ基因型-------------------------------------------- 31
第二節 Xinβ 同質型基因剔除小鼠的體重及心重----------------------- 31
第三節 Xinβ 同質型基因剔除小鼠的傳導速率-------------------------- 32
第四節 Xinβ 同質型基因剔除小鼠左心房組織的電生理特性-------- 33
第五節 超快速延遲整流的鉀離子第電流(IKur)及暫時性向外流的鉀離
子電流(Ito)在同質型基因剔除小鼠左心房中的角色--------- 34
第六節 L 型鈣離子電流(ICa,L)在同質型基因剔除小鼠左心房組織中的
角色-------------------------------------------------------------------- 35
第七節 鈉離子電流(INa)在同質型基因剔除小鼠左心房心肌組織中扮
III
演的角色-------------------------------------------------------------- 36
第八節 探討同質型基因剔除小鼠心房中與lKur 及Ito 相關蛋白質的表
現量-------------------------------------------------------------------- 37
第九節 探討同質型基因剔除小鼠心房中與傳導速度相關的蛋白質表
現量-------------------------------------------------------------------- 38
第十節 探討同質型基因剔除小鼠心房中與鈣離子調控相關的蛋白質
表現量----------------------------------------------------------------- 38
第十一節同質型基因剔除小鼠左心房組織心律不整的發生---------- 39
第十二節Isoproterenol 對於同質型基因剔除小鼠左心房組織心律不整
的影響-----------------------------------------------------------------40
第五章 討論----------------------------------------------------------------------- 60
第一節 同質型心基因剔除小鼠左心房的傳導速率之探討---------- 61
第二節 同質型心基因剔除小鼠和野生型小鼠左心房動作電位之探
討---------------------------------------------------------------------- 64
第三節 同質型心基因剔除小鼠左心房的收縮力調控之探討------- 66
第四節 同質型心基因剔除小鼠心律不整發生率之探討------------- 68
第五節 未來的發展與臨床應用------------------------------------------- 72
第六章 結論----------------------------------------------------------------------- 73
第七章 參考文獻----------------------------------------------------------------- 74

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