臺灣博碩士論文加值系統

在西元2001年美國食品藥品監督管理局已核可將乙型利鈉胜肽(BNP)作為心臟衰竭之治療用藥。然而，在臨床使用後未達預期療效，甚至加速腎臟功能損傷，因此BNP用於心臟衰竭之治療上仍有許多爭議，需待更多基礎研究來進一步釐清。近年來臨床統計發現血液中長期呈現乙型利鈉胜肽較高之個案發生心房顫動的比例明顯較高，科學家推測BNP是扮演著促進心房顫動與纖維化之危險因子，然而其真正機制未明。
本篇研究探討BNP對於心房纖維化及心房顫動影響，以腫瘤壞死因子(TNF-α)注射導致之心房纖維化小鼠為動物模式以及利用心臟手術過程中因建立體外循環而剪下的右心房心耳分離培養出之人類心房肌纖維母細胞為材料進行細胞相關研究。研究發現以TNF-α注射導致心房纖維化之小鼠再給予注射BNP時，會活化基質金屬蛋白酶-2 (MMP-2)表現量及膠原蛋白(collagen)堆積來加劇心房纖維化情形。細胞實驗部分，以BNP處理人類心房肌纖維母細胞亦能觀察到MMP-2表現量增加，更進一步以蛋白合成抑制劑cycloheximide 處理細胞並無發現特殊意義，然而利用蛋白酶體抑制劑MG132 刺激細胞會更增加BNP刺激所造成的MMP-2表現量上升，證明蛋白穩定度及抑制蛋白酶體調控蛋白之降解路徑參與其中。抑制SIRT1表現明顯減少BNP刺激所造成的MMP-2表現量上升，此外免疫螢光染色及免疫沉澱法的結果都指出MMP-2和SIRT1之間具有交互作用，造成MMP-2去乙醯化進而增加蛋白穩定度。最後利用小鼠纖維化心房組織證明SIRT1和MMP-2共定位於細胞質，由實驗結果可推論BNP在心房扮演著促進心房纖維化之作用角色。

B-type natriuretic peptide (BNP) was approved by the US Food and Drug Administration in 2001 for the treatment of heart failure. However, the effects of BNP in clinical applications are controversial and uncertain. Recently, study indicated that high BNP levels are associated with an increased risk of developing atrial fibrillation. In this study, we investigated the direct effects of BNP on TNF--induced atrial fibrosis mice, as well as its effects on human atrial myofibroblasts. We found that injecting TNF--induced mice with recombinant human BNP enhanced atrial fibrosis via MMP-2 expression and collagen accumulation. Furthermore, we found that BNP stimulated MMP-2 expression in human atrial myofibroblasts. Treatment of human atrial myofibroblasts with cycloheximide had no effect on this outcome; however, treatment of cells with MG132 enhanced BNP-induced MMP-2 expression, indicating that protein stability and inhibition of proteasome-mediated protein degradation pathways are potentially involved. Inhibition of SIRT1 significantly decreased BNP-induced MMP-2 expression. Additionally, confocal and co-IP data indicated that BNP-regulated MMP-2 expression are likely to be mediated through direct interaction with SIRT1, which is thought to deacetylate MMP-2 and to increase its protein stability in human atrial myofibroblasts. Finally, we confirmed that SIRT1 is expressed and cytoplasmically redistributed as well as co-localized with MMP-2 in mouse fibrotic atrial tissue. We suggest a possible fibrosis-promoting role of BNP in the atrium, although the antifibrotic properties of BNP in the ventricle have been reported in previous studies, and that the coordination between MMP-2 and SIRT1 in BNP-induced atrial myofibroblasts participates in atrial fibrosis.

目錄
目錄 I
圖表目錄 II
中文摘要 III
英文摘要 IV
第一章、諸論 1
第一節、心臟手術後心房顫動心律不整 1
第二節、心房顫動心律不整及心臟組織的結構重塑 2
第三節、心房纖維母細胞之重要性及其在心房組織結構重塑所扮演之角色 3
第四節、乙型利鈉胜肽(B type Natriuretic Peptides; BNP)之臨床運用及與心房顫動之相關性 6
第五節、菸鹼酸腺嘌呤二核甘酸 在心房顫動中的可能機制 10
第六節、心臟手術與發炎反應 11
第七節、研究目的 13
第八節、本計畫預計提出八個部分的實驗來驗證這個假說 14
壹、合成重組人類乙型利鈉肽（BNP） 14
貳、建立TNFα誘導的心房纖維化小鼠模型，並研究BNP在該過程中的作用 15
參、 人類心房肌纖維母細胞的分離與培養 15
肆、 BNP在人類心房肌纖維母細胞組織細胞外間質重塑作用中的角色 16
伍、從核糖核酸蛋白轉譯層次及蛋白酶體複合物對蛋白質的降解層次探討BNP調控MMP-2表現的機制 16
陸、 探討SIRT1在BNP調控MMP-2表現中的作用 17
柒、 探討在BNP調控MMP-2的過程中，SIRT1是否確實直接作用在MMP-2上，並透過去乙基化穩定MMP-2蛋白的表現 17
捌、上述細胞層面的研究發現在動物活體內驗證 17

第二章、材料與方法 19
第一節、製備人類重組蛋白BNP 19
壹、 構建pGEX-5X-1-humna BNP表現載體 19
貳、 人類重組BNP蛋白的純化 19
參、 環磷酸鳥苷(cGMP)檢驗 20
第二節、動物實驗 21
壹、研究道德聲明 21
貳、動物實驗和分組 21
参、心臟超音波 22
肆、 樣本製備 23
伍、 天狼星紅染色 (Sirius Red staining)、免疫組織化學染色法(immunohistochemistry)及免疫螢光染色法 (immunofluorescent) 23
第三節、細胞實驗 24
壹、 試劑與藥品 24
貳、研究倫理及病人樣本資料採集 25
參、 心房肌纖維母細胞分離、培養及鑑定 25
肆、 即時定量聚合酶連鎖反應(quantitative real-time polymerase chain reaction) -分析mRNA的表現 26
伍、 細胞毒性試驗(MTT assay) 27
陸、 西方墨點法(Western analysis)-分析蛋白質的表現 28
柒、 明膠基質金屬蛋白酵素活性測試(gelatin-zymography) - 分析MMP2蛋白質活性 29
捌、 透過shRNA轉染抑制SIRT1基因表達 30
玖、細胞免疫螢光染色法(immunofluorescence；IF) 30
拾、免疫共沉澱法 31
拾壹、統計分析 31
第三章、結果 32
第一節、人類重組蛋白BNP確實能刺激cGMP活性 32
第二節、建立誘導心房纖維化發生之動物模式，並觀察心房纖維化情形 33
第三節、人類心肌纖維母細胞分離及培養，鑑定及確認細胞可表現肌纖維母細胞標記蛋白(Marker) Vimentin及α-smooth muscle actin和具有BNP接受器之表現 35
第四節、BNP透過調控人類心肌纖維母細胞的MMP-2表達，參與心房組織細胞外基質重塑過程 35
第五節、BNP能夠刺激MMP-2的表現，可能透過蛋白質穩定性和抑制人類心肌纖維母細胞中蛋白酶體誘導的蛋白質降解途徑 37
第六節、SIRT1參與BNP調控人類心房肌纖維母細胞中MMP-2的表現 38
第七節、人類心房肌纖維母細胞中SIRT1透過與MMP-2的相互作用和去乙基化來調節BNP誘導的MMP-2表現量增加 39
第八節、小鼠纖維化心房組織中SIRT1的表現在細胞質重新分佈，以及與MMP-2的共定位 42
第四章、討論 44
第五章、結論 50
表 51
圖 52
參考文獻 89
論文發表 105







表目錄
表 一:實驗動物心臟超音波數值 53


圖目錄

圖 一、心臟手術中於建立體外循環(extra-corporal circulation; ECC)而切除的局部心房組織示意圖。 54
圖 二、 SDS-PAGE/ Coomassie blue staining，結果顯示本實驗室已成功製作出BNP重組蛋白。 55
圖 三、透過胺基酸定序檢核本實驗室製作出的BNP重組蛋白，並比對BNP核酸序列。 56
圖 四、以環磷酸鳥苷(cGMP)競爭性的免疫吸附分析法(EIA)檢測細胞內cGMP 的活化情形。 57
圖 五、來自小鼠的心房組織的心房肌纖維母細胞的生長狀。 58
圖 六、以RT-PCR檢測小鼠心房肌纖維母細胞是否具有BNP的受器蛋白。 59
圖七、以自製人類重組BNP蛋白(濃度10-7或 10-6 M)刺激小鼠心房肌纖維母細胞後，細胞內環磷酸鳥苷(cGMP)有被活化情形。 60
圖八、包含了從心臟乳突肌水平的短軸視圖2D引導M-mode描繪的左心室直徑，和二尖瓣血流流速從四腔室切面所示的E、A波。 61
圖九、犧牲當天從實驗小鼠取得的心臟照片（左）。將心臟重量量化圖（右）。數據為三隻小鼠的平均值±SEM。 62
圖十、對實驗動物的右心房組織病理切片進行天狼星紅染色。 63
圖十一、使用MMP-2抗體對實驗動物的右心房組織病理學切片進行免疫組織化學染色。 64
圖十二、從人類的心房組織分離及培養的肌纖維母細胞。 65
圖十三、將人類心房組織培養出之心房肌纖維母細胞透過α-SMA和vimentin抗體進行西方墨點法。 66
圖十四、將人類心房組織培養出之心房肌纖維母細胞以免疫螢光染色法透過共軛焦顯微鏡加以分析。 67
圖十五、分離培養的人類心肌纖維母細胞都具有利鈉胜肽受器A (NPRA)的表現，並確定細胞具有cGMP活性。 68
圖十六、使用細胞毒性試驗(MTT assay)來確認本實驗室製作出之GST-BNP重組蛋白在作用濃度下(10-6 M)不具細胞毒性。 69
圖十七、透過即時定量聚合酶連鎖反應(RT-PCR)檢驗COL1A1在人類心肌纖維母細胞內訊息核糖核酸(mRNA)的表現。 70
圖十八、透過即時定量聚合酶連鎖反應(RT-PCR)檢驗MMP-2在人類心肌纖維母細胞內訊息核糖核酸(mRNA)的表現。 71
圖十九、在GST-BNP處理人類心肌纖維母細胞24小時後，以西方墨點法分析COL1A1及MMP-2蛋白質層面表現。 72
圖二十、在GST-BNP處理人類心肌纖維母細胞24及48小時後，以西方墨點法分析MMP-2蛋白質層面表現。 73
圖二十一、 使用明膠基質金屬蛋白酵素活性測試(gelatin-zymography)來分析GST-BNP處理人類心肌纖維母細胞後MMP-2蛋白活性。 74
圖二十二、使用來自小鼠的心肌纖維母細胞重複和確認，在GST-BNP處理細胞24及48小時後，以西方墨點法分析MMP-2蛋白質層面表現，以及使用明膠基質金屬蛋白酵素活性測試(gelatin-zymography)分析MMP-2蛋白活性。 75
圖二十三、使用CHX（cycloheximide, a eukaryote protein synthesis inhibitor）或MG132（an inhibitor of 26S proteasome complex）處理人類心肌纖維母細胞，以觀察GST-BNP 對MMP-2蛋白的調控影響。 77
圖二十四、以10-6M GST-BNP處理人類心肌纖維母細胞18或36小時，檢視SIRT1的表現。 79
圖二十五、採用兩總不同方式抑制人類心肌纖維母細胞SIRT1的表現，藉此進一步測定SIRT1受到抑制後是否改變GST-BNP對MMP-2蛋白的調控。 81
圖二十六、藉由shRNA轉染抑制人類心肌纖維母細胞SIRT1的表現，藉此進一步測定SIRT1受到抑制後是否改變GST-BNP對MMP-2蛋白的調控。 83
圖二十七、使用免疫螢光染色後在共聚焦顯微鏡下觀察人類心房肌纖維母細胞中SIRT1與MMP-2的相互作用。 85
圖二十八、採用免疫共沉澱法(Co-IP)用於觀察人類心房肌纖維母細胞中SIRT1與MMP-2的相互作用。 86
圖二十九、用抗乙基化離氨酸抗體進行西方墨點法來測定MMP2的乙基化程度。 87
圖三十、小鼠心房組織中經TNF-α及GST-BNP處置後SIRT1及αSMA的表現。 88
圖三十一、小鼠心房組織中經TNF-α及GST-BNP處置後，SIRT1表現在小鼠心房細胞外基質重塑過程中並重新分佈於細胞質，且與MMP-2共定位。 89
圖三十二、研究成果示意圖。 90

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