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研究生:張佐維
研究生(外文):Tso-Wei Chang
論文名稱:磷酸比哆醛抑制血小板ADP接受器之研究
論文名稱(外文):Study on the inhibition of platelet ADP receptors by pyridoxal-5'-phosphate
指導教授:張素瓊張素瓊引用關係
指導教授(外文):Sue-Joan Chang
學位類別:碩士
校院名稱:國立成功大學
系所名稱:生物學系碩博士班
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:105
中文關鍵詞:ADP 接受器磷酸比哆醛血小板
外文關鍵詞:ADP receptorpyridoxal-5'-phosphateplatelet
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ADP是最早被發現的血小板致凝物(agonist),且所誘發的血小板反應在血液恆定與血栓症中最為重要。磷酸比哆醛(pyridoxal-5-phosphate, PLP)是維生素B6在體內的主要活化形式,在體外與體內系統均被發現具有抑制動物或人的ADP誘發性血小板凝集作用。ADP誘發血小板活化反應,是透過ADP與血小板表面ADP接受器結合所引起的一連串訊息傳遞反應而產生。本研究室過去對維生素B6抗血小板機制的研究發現,PLP可抑制ADP誘發性血小板凝集作用,推測PLP可能會與ADP競爭其接受器位置。目前已知血小板上ADP接受器分為三種,P2X1、P2Y1和P2T(P2Y12)。P2X1是離子形通道接受器,可引起由ADP所誘發的細胞外鈣離子快速內流機制,不過並未發現會造成血小板凝集。ADP與P2Y1接受器結合後,藉由Gq protein,活化phospholipase C(PLC),進而產生IP3引起細胞內鈣離子的釋放。P2T接受器藉由Gi protein,抑制adenylate cyclase活化,進而調控ADP誘發血小板胞內cAMP濃度下降。利用ADP接受器的拮抗劑(antagonist)可抑制訊息的傳遞,進而抑制ADP誘發性血小板反應。因此,本研究擬利用P2Y1拮抗劑(adenosine 2'-phosphate 5'-phosphate;A2P5P)與P2T抑制劑(ticlopidine)及P2X1接受器專一性活化物(a,b-methylene ATP;a,b-MeATP)來探討PLP對ADP誘發性的血小板變化,包括血小板凝集、P-selectin表現、cAMP濃度變化、ATP釋放與胞內鈣離子流動變化,進而探討PLP抑制ADP誘發性血小板活化與凝集的可能機制。利用血小板凝集儀(aggregometer)偵測血小板凝集,利用冷光血小板凝集儀(lumi-aggregometer)偵測ATP釋放,利用流式細胞儀(flow cytometer)偵測P-selectin釋放與鈣離子的流動,利用酵素免疫分析(enzyme immunoassay)偵測cAMP濃度。
結果顯示,PLP無法抑制 a,b-MeATP(P2X1接受器活化物)誘發性ATP釋放與胞外鈣離子內流。1 mM PLP透過P2T與P2Y1接受器分別顯著抑制約13 ~ 22 % 及27 ~ 36 % 的ADP誘發性血小板凝集。1 mM PLP透過P2T與P2Y1接受器分別顯著抑制約57 % 及10 % 的ADP誘發性血小板P-selectin表現量。1 mM PLP透過P2T與P2Y1接受器分別顯著抑制約37 % 及19 % 的ADP誘發性血小板ATP釋放。1 mM PLP透過P2Y1接受器顯著抑制約32 % 的ADP誘發性胞內鈣離子釋放量。1 mM PLP透過P2T接受器顯著提昇約29 % 的ADP誘發性血小板cAMP濃度。經PLP處理後ADP誘發性血小板凝集與活化指標(P-selectin、ATP、胞內鈣離子釋放、cAMP)呈顯著相關性(r=0.6286,p<0.05;r=0.8017,p<0.001;r=0.8765,p<0.001;r=-0.7186,p<0.001)。
本研究結論,PLP可抑制ADP誘發性血小板活化,進而抑制凝集反應。PLP透過P2T與P2Y1接受器抑制ADP誘發性P-selectin表現、ATP釋放等血小板活化與凝集反應,透過P2T接受器抑制ADP誘發性cAMP濃度下降,透過P2Y1接受器抑制ADP誘發性胞內鈣離子釋放。PLP抑制血小板機制是透過P2T與P2Y1接受器,而不是透過P2X1接受器抑制ADP誘發性血小板活化。
Adenosine 5-diphosphate (ADP) was the first agonist found to be responsible for platelet response and for playing a crucial role in hemostasis and thrombosis. Pyridoxal-5-phosphate (PLP), the active form of vitamin B6, has been found to inhibit ADP-induced platelet aggregation both in vitro and in vivo in animal and human studies. ADP-induced platelet activation results from a series of signal transductions caused by the binding of ADP to ADP receptors on platelet membranes. A previous study from our laboratory showed that PLP inhibited ADP-induced platelet aggregation, suggesting that PLP may compete with ADP to bind to ADP receptors. Three known subtypes of ADP receptors were found on platelet membranes and classified as P2X1, P2Y1 and P2T (P2Y12) receptors. The P2X1 receptor (a ligand-gated ion channel) mediates rapid transient calcium influx, but has not been found to contribute to platelet aggregation. The P2Y1 receptor activates phospholipase C (PLC), via Gq. This accounted for most of the elevation in cytosolic calcium induced by ADP, via formation of IP3, which resulted in the release of calcium from intracellular stores. The P2T receptor mediates a decreased cyclic AMP level in response to ADP through the inhibition of adenylate cyclase via Gi. Using ADP receptors, antagonists, through the inhibition of signal transduction, could inhibit ADP-induced platelet aggregation. The purpose of this study was to investigate the anti-platelet mechanism of PLP on ADP-induced platelet responses. The responses studied included platelet aggregation, P-selectin expression, intracellular cAMP concentration, ATP release and intracellular calcium mobilization. The receptors used included the P2Y1 antagonist (A2P5P), P2T inhibitor (ticlopidine), and the P2X1 selective agonist a,b-methylene ATP (a,b-MeATP). Platelet aggregation was measured by aggregometer. P-selectin expression and calcium mobilization were determined by flow cytometer. ATP release was measured by lumi-aggregometer. Intracellular cAMP concentration was measured by enzyme immunoassay.
The results indicated that PLP did not inhibit a,b-MeATP-induced ATP release and extracellular calcium influx. All PLP studies were done at a concentration of 1 mM of PLP. The findings include: PLP significantly inhibited ADP-induced platelet aggregation by 13 ~ 22 % and 27 ~ 36 % through P2T and P2Y1 receptors, respectively. Furthermore, PLP significantly inhibited ADP-induced platelet P-selectin expression by 57 and 10 % through P2T and P2Y1 receptors, respectively. In addition, PLP significantly inhibited ADP-induced platelet ATP release by 37 and 19 % through P2T and P2Y1 receptors, respectively. And PLP significantly inhibited ADP-induced platelet intracellular calcium release by 32 % through the P2Y1 receptor. And finally, PLP significantly increased ADP-induced platelet cAMP concentration by 29 % through the P2T receptor. Inhibition of PLP on ADP-induced platelet aggregation showed significant correlation with ADP-induced platelet activation indexes, including P-selectin, ATP, calcium release and cAMP (r = 0.6286, p<0.05; r = 0.8017, p<0.001; r = 0.8765, p<0.001; r = -0.7186, p<0.001).
In conclusion, PLP can inhibit ADP-induced platelet activation and platelet aggregation. The anti-mechanism of PLP to inhibit ADP-induced platelet activation (including P-selectin expression and ATP release via both P2T and P2Y1, intracellular mobilization via P2Y1, and an increased cAMP via P2T) and aggregation was through P2T and P2Y1 receptors, not through the P2X1 receptor.
中文摘要………………………………………………………… Ⅰ
英文摘要………………………………………………………… Ⅳ
致謝……………………………………………………………… Ⅷ
目錄……………………………………………………………… Ⅸ
表目錄………………………………………………………… ⅩⅠ
圖目錄………………………………………………………… ⅩⅡ
附圖目錄……………………………………………………… ⅩⅤ
縮寫符號……………………………………………………… ⅩⅥ
第一章、 前言…………………………………………………… 1
第二章、 文獻探討……………………………………………… 4
第三章、 實驗材料及方法……………………………………… 14
第四章、 結果…………………………………………………… 30
第五章、 討論…………………………………………………… 41
參考文獻………………………………………………………… 50
表次……………………………………………………………… 63
圖次……………………………………………………………… 64
附圖次…………………………………………………………… 100
自述……………………………………………………………… 105
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