臺灣博碩士論文加值系統

臨床研究發現心衰竭為雙相情緒障礙症病人突發性心因性死亡的主要風險因子，國內以心臟超音波調查發現服用鋰鹽之雙相情緒障礙症病人其心臟功能優於未服用鋰鹽者，顯示鋰鹽除神經細胞保護作用外可能在雙相情緒障礙症病人具有心臟保護潛力；心臟纖維化為心衰竭的重要因子，然目前文獻仍未探討鋰鹽能否改善心臟纖維化。研究發現快速動眼期睡眠剝奪會促發雙相情緒障礙症病人躁期發作，因此快速動眼期睡眠剝奪為現今躁症主要動物模型之一，此外，快速動眼期睡眠剝奪會誘發大鼠心功能異常以及心臟纖維化等病變，因此本研究預計利用快速動眼期睡眠剝奪大鼠作為研究模型，探討鋰鹽能否改善快速動眼期睡眠剝奪大鼠心臟纖維化以及相關訊息傳遞路徑，並且為進一步了解鋰鹽能否具有改善人類心臟纖維化的潛力，本研究亦利用人類心臟纖維母細胞研究鋰鹽是否抑制人類心臟纖維母細胞的活性以及其機轉。實驗結果發現，相較未服用LiCl之快速動眼期睡眠剝奪大鼠，每日經口管餵四週LiCl 1 mmol/kg之快速動眼期睡眠剝奪大鼠其左心室收縮功能異常及心臟纖維化程度較輕微，此外，在乙型轉化生長因子(transforming growth factor beta)、血管收縮素(angiotensin)、以及鈣池調控鈣離子流(store-operated calcium entry)等促纖維化訊息傳遞路徑的表現量較低，進一步以人類心臟纖維母細胞進行實驗，發現相較於對照組，給予LiCl 0.1 mM二十四小時的人類心臟纖維母細胞移行能力、膠原蛋白製造能力、鈣池調控鈣離子流、以及calcium release-activated calcium channel protein 1 (Orai1)表現量較低，合併給予Orai1抑制劑2-APB 10 µM及LiCl 0.1 mM相較單獨給予LiCl 0.1 mM未額外抑制鈣池調控鈣離子流，顯示鋰鹽可能經由抑制Orai1表現以及減低鈣池調控鈣離子流來改善心臟纖維化和心臟功能，此結果能提供臨床研究人員進一步試驗鋰鹽心臟保護性的基礎研究證據，以利降低雙相情緒障礙症病人過高的心臟疾病死亡率。

Emerging clinical studies have shown that beyond the neuroprotection, lithium may be cardioprotective for patients with bipolar disorder. Despite the fact that cardiac fibrosis is a detrimental factor of heart failure, few studies so far have evaluated whether lithium has anti-fibrotic effects using an experimental model with translational relevance to the bipolar disorder population. In clinic, rapid eye movement (REM) sleep deprivation has been well recognized as a trigger for mania. Furthermore, REM sleep deprivation induces cardiac fibrosis and contractile dysfunction. Therefore, the first aim of this study was to investigate whether lithium inhibited fibrogenesis in myocardium of rats deprived of REM sleep. Additionally, this study also aimed to elucidate anti-fibrotic mechanisms of lithium in human cardiac fibroblasts. The animal study showed that REM sleep-deprived rats displayed a greater contractile dysfunction and fibrosis in left ventricles than did the control and lithium-treated REM sleep-deprived rats (LiCl 1 mmol/kg/day administered by oral gavage for a total of 4 weeks). In addition, REM sleep-deprived hearts activated pro-fibrotic signaling and upregulated ion channels of store-operated Ca2+ entry (SOCE) compared to the control and lithium-treated REM sleep-deprived hearts. As for the cellular study, treatment of LiCl 0.1 mM for 24 hours reduced migration and collagen synthesis capability of human cardiac fibroblasts compared to the control cells. Furthermore, LiCl 0.1 mM for 24 hours downregulated expression levels of calcium release-activated calcium channel protein 1 (Orai1) and attenuated thapsigargin-induced SOCE in human cardiac fibroblasts. Combination of 2-APB 10 µM and LiCl 0.1 mM decreased migration and collagen synthesis ability as well as thapsigargin-induced SOCE in human cardiac fibroblasts to a similar extent as that observed in the LiCl (0.1 mM)-treated fibroblasts. Taken together, this study suggested that lithium improved myocardial systolic function and reduced fibrogenesis through the downregulation of Orai1 expression and SOCE.

中文摘要 i
英文摘要 iii
第一章、緒論
第一節、雙相情緒障礙症病人的臨床特徵及精神表現 1
第二節、雙相情緒障礙症病人的心臟血管共病與死亡風險 2
第三節、雙相情緒障礙症病人高心臟血管共病及死亡的相關因素 4
第四節、近年臨床研究顯示鋰鹽可能具有心臟保護作用 6
第五節、現今鋰鹽心臟保護作用的機轉研究與侷限 7
第六節、心臟纖維化的分子機制 9
第七節、以快速動眼期睡眠剝奪大鼠作為研究鋰鹽心臟保護作用的模型 11
第八節、研究假設和目的 13
第二章、研究方法與材料
第一節、動物實驗
(一)快速動眼期睡眠剝奪大鼠模型 14
(二)行為觀察與分析 15
(三)心臟結構與功能分析 15
(四)心臟纖維組織定量 16
(五)西方墨點法 16
第二節、細胞實驗
(一)人類心臟纖維母細胞培養 19
(二)人類心臟纖維母細胞移行能力測定 19
(三)人類心臟纖維母細胞增殖能力測定 19
(四)人類心臟纖維母細胞小分子干擾核糖核酸轉染 20
(五)即時聚合酶連鎖反應 20
(六)鈣離子螢光成像 21
(七)西方墨點法 22
第三節、統計方法 24
第三章、研究結果
第一節、動物實驗
(一)鋰鹽對快速動眼期睡眠剝奪大鼠心臟躁症行為的作用 25
(二)鋰鹽對快速動眼期睡眠剝奪大鼠心臟結構與功能的作用 25
(三)鋰鹽對快速動眼期睡眠剝奪大鼠心臟組織的作用 25
(四)鋰鹽對快速動眼期睡眠剝奪大鼠心臟TGF-β訊息傳遞路徑的作用 26
(五)鋰鹽對快速動眼期睡眠剝奪大鼠心臟angiotensin II訊息傳遞路徑的作用 26
(六)鋰鹽對快速動眼期睡眠剝奪大鼠心臟鈣池調控鈣離子流通道的作用 26
第二節、細胞實驗
(一)鋰鹽對人類心臟纖維母細胞移行能力的作用 28
(二)鋰鹽對人類心臟纖維母細胞膠原蛋白製造能力的作用 28
(三)鋰鹽對人類心臟纖維母細胞移行增殖能力的作用 28
(四)鋰鹽對人類心臟纖維母細胞鈣池調控鈣離子流的作用 28
(五)鋰鹽對人類心臟纖維母細胞Orai1以及STIM1表現的作用 29
(六)鋰鹽對人類心臟纖維母細胞TRPC表現的作用 29
(七)鋰鹽對人類心臟纖維母細胞Akt/mTOR訊息傳遞路徑表現的作用 30
(八)鋰鹽對人類心臟纖維母細胞GSK-3β/β-catenin訊息傳遞路徑表現的作用 30
(九)合併鋰鹽及Orai1抑制劑2-APB對人類心臟纖維母細胞移行能力的作用 31
(十)合併鋰鹽及Orai1抑制劑2-APB對人類心臟纖維母細胞膠原蛋白製造能力的作用 31
(十一)合併鋰鹽及Orai1抑制劑2-APB對人類心臟纖維母細胞鈣池調控鈣離子流的作用 31
第四章、討論
第一節、研究主要發現 33
第二節、鋰鹽經由降低鈣池調控鈣離子流的抗纖維化作用 34
第三節、鋰鹽經由抑制angiotensin II及TGF-β訊息傳遞路徑的抗纖維化作用 37
第四節、Akt/mTOR訊息傳遞路徑在鋰鹽心臟保護作用的探討 38
第五節、GSK-3β/β-catenin訊息傳遞路徑在鋰鹽心臟保護作用的探討 39
第六節、鋰鹽對心臟離子流的可能影響 41
第七節、鋰鹽心臟保護作用的治療濃度 42
第八節、研究限制 43
第五章、結論與展望
第一節、結論 44
第二節、展望 45
參考文獻 46
圖一、有無接受鋰鹽治療的快速動眼期睡眠剝奪大鼠躁症行為表現 64
圖二、有無接受鋰鹽治療的快速動眼期睡眠剝奪大鼠左心室結構 65
圖三、有無接受鋰鹽治療的快速動眼期睡眠剝奪大鼠左心室收縮功能 66
圖四、有無接受鋰鹽治療的快速動眼期睡眠剝奪大鼠心臟重量對體重比值 67
圖五、有無接受鋰鹽治療的快速動眼期睡眠剝奪大鼠心臟膠原蛋白體積分率 68
圖六、有無接受鋰鹽治療的快速動眼期睡眠剝奪大鼠左心室transforming growth factor beta表現量 69
圖七、有無接受鋰鹽治療的快速動眼期睡眠剝奪大鼠左心室Smad 2/3表現量 70
圖八、有無接受鋰鹽治療的快速動眼期睡眠剝奪大鼠左心室alpha-smooth muscle actin表現量 71
圖九、有無接受鋰鹽治療的快速動眼期睡眠剝奪大鼠左心室angiotensin II receptor 1表現量 72
圖十、有無接受鋰鹽治療的快速動眼期睡眠剝奪大鼠左心室phosphorylated nuclear factor kappa B表現量 73
圖十一、有無接受鋰鹽治療的快速動眼期睡眠剝奪大鼠左心室鈣池調控鈣離子流(store-operated calcium entry)通道表現 74
圖十二、有無接受鋰鹽治療的快速動眼期睡眠剝奪大鼠左心室transient receptor potential canonical channel表現 75
圖十三、給予LiCl 0.1 mM及1.0 mM二十四小時的人類心臟纖維母細胞移行能力 76
圖十四、給予LiCl 0.1 mM及1.0 mM二十四小時的人類心臟纖維母細胞膠原蛋白製造能力 77
圖十五、給予LiCl 0.1 mM及1.0 mM二十四小時的人類心臟纖維母細胞增殖能力 78
圖十六、給予LiCl 0.1 mM二十四小時的人類心臟纖維母細胞鈣池調控鈣離子(store-operated calcium entry)表現 79
圖十七、給予LiCl 1.0 mM二十四小時的人類心臟纖維母細胞鈣池調控鈣離子(store-operated calcium entry)表現 80
圖十八、人類心臟纖維母細胞calcium release-activated calcium channel protein 1 (Orai1)小分子干擾核糖核酸轉染 81
圖十九、給予LiCl 0.1 mM及1.0 mM二十四小時的人類心臟纖維母細胞calcium release-activated calcium channel protein 1以及stromal interaction molecule 1表現量 82
圖二十、給予LiCl 0.1 mM及1.0 mM二十四小時的人類心臟纖維母細胞transient receptor potential canonical channel表現量 83
圖二十一、給予LiCl 0.1 mM及1.0 mM二十四小時的人類心臟纖維母細胞protein kinase B (Akt)/mammalian target of rapamycin (mTOR)訊息傳遞路徑表現 84
圖二十二、給予LiCl 0.1 mM及1.0 mM二十四小時的人類心臟纖維母細胞glycogen synthase kinase-3 beta (GSK-3β)/β-catenin訊息傳遞路徑表現 85
圖二十三、合併給予LiCl 0.1 mM及Orai1抑制劑2-APB對人類心臟纖維母細胞移行能力的作用 86
圖二十四、合併給予LiCl 0.1 mM及Orai1抑制劑2-APB對人類心臟纖維母細胞膠原蛋白製造能力的作用 87
圖二十五、合併給予LiCl 0.1 mM及Orai1抑制劑2-APB對人類心臟纖維母細胞鈣池調控鈣離子流(store-operated calcium entry)的作用 88
圖二十六、鋰鹽抑制心臟纖維化之機轉示意圖 89

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