低劑量亞砷酸鈉誘引第一型血紅素氧化?調控路徑之研究; Signaling pathways involved in Heme Oxygenase-1 induction by low doses of arsenite

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Title:	低劑量亞砷酸鈉誘引第一型血紅素氧化?調控路徑之研究;Signaling pathways involved in Heme Oxygenase-1 induction by low doses of arsenite
Authors:	張瑞娟;Jui-Chuan Chang
Contributors:	生命科學研究所
Keywords:	第一型血紅素氧化酶;亞砷酸鈉;arsenite;Heme Oxygenase-1
Date:	2002-06-18
Issue Date:	2009-09-22 10:17:34 (UTC+8)
Publisher:	國立中央大學圖書館
Abstract:	中文摘要砷化物是人類的致癌物質，會引起如動脈粥狀硬化、烏腳病等一些心臟血管疾病。第一型血紅素氧化酶( Heme oxygenase – 1, HO-1) 能被許多物質所誘導出來，包括血色素、氧化性壓力、熱刺激、生長因子以及一些重金屬，如砷化物，鎘金屬。其功能是代謝血紅素產生鐵離子、膽紅素、與一氧化碳。然而其中膽紅素具有抗氧化的功能，因此第一型血紅素氧化酶的生成，被認為是當細胞遭受到氧化性傷害時，被誘導出來保護細胞免於氧化性傷害。研究發現在牛的大動脈血管細胞與人類成纖細胞中，低濃度(1 ?M)亞砷酸鈉會誘引第一型血紅素氧化酶蛋白質的表現。為了探討其誘導途徑與參與的分子，本文採用了許多抑制劑。其中轉錄型抑制劑，adriamycin 與actinomycin D能明顯的抑制低濃度亞砷酸鈉誘引第一型血紅素氧化酶蛋白質的表現，因此低濃度的亞砷酸鈉誘導第一型血紅素氧化酶，是先經由轉錄，再經由轉譯成蛋白質之路徑。其他抑制劑如Calphostin C (蛋白質激酶 C，PKC抑制劑); H8 和H89(蛋白質激 A ，PKA抑制劑); quinacrine(磷質脂A2 抑制劑); BATPA/AM(鈣離子螯合劑)，皆能個別的抑制低濃度亞砷酸鈉誘引第一型血紅素氧化酶蛋白質的表現。然而其中Quinacrine與BATPA/AM的抑制能力似乎是抑制RNA的形成。因此quinacrine 和BATPA/AM抑制亞砷酸鈉誘導第一型血紅素氧化酶的能力，與抑制磷質脂A2和鈣離子的訊息傳遞之路徑無關。而在PKC抑制劑方面，另外使用Bisindolylmaleimide I、D-erythio-sphingosine、Chelerythrine chloride卻不能有效抑制被誘引第一型血紅素氧化酶蛋白質表現，因此Calphostin C似乎也並非單純經由抑制PKC的路徑去抑制低濃度亞砷酸鈉誘引第一型血紅素氧化酶的表現。目前的結果指出，在內皮細胞與人類成纖細胞中，PKA 似乎參與低濃度亞砷酸鈉誘引第一型血紅素氧化酶蛋白質調控路中。然而還是需要再做進一步的證實。 Abstract Arsenite (As (III)) is a human carcinogen, also known to increase the risk of cardiovascular diseases, such as atherosclerosis and blackfoot disease. Heme oxygenase-1 (HO-1) is induced by a variety of agents, such as heme, oxidative stress, heat shock, cytokines, and some heavy metals (arsenite and cadmium). HO-1 catalyzes heme degradation into iron, biliverdin, and carbon monoxide. Biliverdin is subsequently converted to bilirubin by bilirubin reductase since bilirubin has antioxidant properties, HO-1 is considered to play a protective role against oxidative injury. In this thesis, how HO-1 is induced by low dose of sodium arsenite (< 1 ?M) in bovine aortic endothelial cells and human fibroblasts is investigated. To examine which pathway or signaling molecule involved in low dose sodium arsenite-mediated induction of HO-1, several inhibitors we were used adopted in this study. The results show that both adriamycin and actionmycin D decrease 1 ?M sodium arsenite-induced HO-1 expression, indicating that HO-1 expression induced by 1 ?M sodium arsenite is via transcription and translation. Pre-treatments of BAEC and HFW with Calphostin C (an inhibitor of protein kinase C), H8 and H89 (inhibitor of protein kinase A), quinacrine (an inhibitor of phospholipase A2), BATPA/AM (an calcium chelater) reduce HO-1 expression levels by 1 ?M As (III). Unfortunately, quinacrine and BATPA/AM also inhibit RNA synthesis. The inhibitory effects of quinacrine and BATPA/AM on arsenite-induced HO-1 expression are unlikely due to inhibition of phospholipase A2 and calcium, respectively. Since other inhibitors of PKC family, such as bisindolylmaleimide I, D-erythio-sphingosine and chelerythrine chloride showed no effect on HO-1 induction by 1 ?M As (III), therefore Calphostin C is also not simply via PKC inhibition to decrease HO-1 expression. The present results imply that PKA is probably involved in low dose sodium arsenite-induced HO-1 expression in BAEC and HFW. However, further confirmation is required.
Appears in Collections:	[Graduate Institute of Life Science] Electronic Thesis & Dissertation

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