以快速動眼期睡眠剝奪大鼠及人類心臟纖維母細胞研究鋰鹽心臟保護作用之分子機轉

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題名:	以快速動眼期睡眠剝奪大鼠及人類心臟纖維母細胞研究鋰鹽心臟保護作用之分子機轉 Insights into the molecular mechanisms of lithium on cardioprotection in rapid eye movement sleep deprivation
作者:	陳抱寰 CHEN, PAO-HUAN
貢獻者:	臨床醫學研究所博士班高玉勳
關鍵詞:	鋰鹽;躁症;快速動眼期睡眠剝奪;人類心臟纖維母細胞;促纖維化訊息傳遞路徑;乙型轉化生長因子;血管收縮素;鈣池調控鈣離子流 lithium;mania;rapid eye movement sleep deprivation;human cardiac fibroblast;pro-fibrotic signaling;transforming growth factor beta;angiotensin II;store-operated Ca2+ entry
日期:	2022-12-27
上傳時間:	2023-12-07 11:08:33 (UTC+8)
摘要:	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 ?M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 ?M 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.
描述:	博士指導教授:高玉勳委員:張世霖委員:林永國委員:李亭儀委員:陳耀昌委員:高玉勳
資料類型:	thesis
顯示於類別:	[臨床醫學研究所] 博碩士論文

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