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研究生:林維國
研究生(外文):Wei Kuo Lin
論文名稱:尿壓素對人類橈動脈平滑肌細胞膜上酸鹼運輸蛋白的作用
論文名稱(外文):Effects of Urotensin II on Intracellular pH Regulators in Human Radial Artery Smooth Muscle Cells
指導教授:羅時鴻羅時鴻引用關係
指導教授(外文):Shin Hurng Loh
學位類別:碩士
校院名稱:國防醫學院
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:87
中文關鍵詞:尿壓素橈動脈平滑肌細胞酸鹼運輸蛋白冠狀動脈血管收縮胜肽腎上腺素心血管
外文關鍵詞:NHENHSAECHELHSurotensin IIpHiradial artery smooth muscle cells
相關次數:
  • 被引用被引用:0
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  • 收藏至我的研究室書目清單書目收藏:0
背景
細胞內 pH 值(intracellular pH, pHi)的改變會影響到許多細胞的正常功能,諸如細胞大小、酵素的活性等。一般哺乳動物細胞中常見的酸鹼調控蛋白像是鈉離子與氫離子交換蛋白(Na+-H+ exchanger;NHE)、鈉離子與重碳酸根離子協同蛋白(Na+-HCO3- symportor;NHS)、氯離子與氫氧根離子交換蛋白(Cl--OH- exchanger;CHE)、氯離子與重碳酸根離子交換蛋白(Cl--HCO3- exchanger;AE)以及乳酸與氫離子協同蛋白(Lactate--H+ symportor;LHS)。有研究指出尿壓素(Urotensin II;U-II)在患有心血管疾病病人的血中濃度偏高,尿壓素是人體內自然產生的胜肽具有強力的血管收縮作用,其血管收縮強度甚至比血管內皮素I、血管緊縮素 II以及正腎上腺素都還高。而橈動脈是冠狀動脈繞道手術中一條相當重要的血管材料,本實驗室之前已在人類橈動脈平滑肌細胞上證明了排酸蛋白的存在(NHE 及 NHS),但是目前還沒有確定有哪些排鹼調控蛋白的存在。因此本實驗的研究目的如下(1)定性在人類橈動脈平滑肌細胞上的排鹼調控蛋白。(2)探討不同濃度的尿壓素對人類橈動脈平滑肌細胞上的酸鹼調控蛋白活性之影響。(3)觀察及比較不同心臟外科常見疾病的血中尿壓素濃度。
實驗材料與方法
使用組織貼片法培養人類橈動脈平滑肌細胞並利用免疫細胞染色法鑑定之。在整個實驗過程中,細胞 pHi 的測定將運用顯微螢光技術搭配對氫離子敏感的螢光染劑(2’,7’-Bis-(2-carboxyethyl)-5(6)-carboxy-fluorescein-acetoxymethyl ester;BCECF-AM)來進行。血中尿壓素的濃度則是用Enzyme-Link ImmunoSorbent Assay(ELISA)測量。
結果
1. 成功培養並鑑定人類橈動脈平滑肌細胞。
2. 在 HEPES 緩衝溶液下,給予 3 pM~100 nM 尿壓素對細胞的 pHi 沒有影響。
3. 在 CO2/HCO3- 緩衝溶液下,給予 10、30 以及 100 nM 尿壓素可以降低細胞 pHi(~ - 0.06 pH unit;P<0.05, n=7),但此酸化作用並沒有劑量依存性。
4. 在 HEPES 緩衝溶液下,3、10、30、100、300 以及 1000 pM 尿壓素可以增加 NHE 活性(+20%;+32%;+55%;+86%;+89% 以及+91%, P<0.05. n=5)且觀察到具有劑量依存性。但意外的給予更高劑量的尿壓素(10~100 nM)時只有增加 NHE 的活性約 +60%(P<0.05, n=5),所以尿壓素增加 NHE 的活性是以 bi-phasic 的形式存在。
5. 實驗首次證明人類橈動脈平滑肌細胞上存在有 AE、CHE 兩種排鹼蛋白,且各佔了 48%以及 26%的總排鹼能力。
6. 在 HEPES 緩衝溶液下,(3~100 nM)尿壓素可以增加 CHE 的活性(+24%;+32%;+36%;+56%及+19%)且有劑量依存性。
7. 在有心衰竭的主動脈瓣、二尖瓣、三尖瓣以及動脈相關疾病等組別的血清中尿壓素濃度分別為(2443、2206、2974以及1078 pM);沒有心衰竭的冠狀動脈繞道一條、二條、三條、動脈相關疾病、二尖瓣以及三尖瓣疾病等組別分別為(884、681、540、425、652 以及501 pM)。正常研究生組血清中尿壓素約 210 pM,相較於病人組均低很多,而心衰竭的病人組含量最高約 2291 pM。
結論
1. 成功培養出人類橈動脈平滑肌細胞並鑑定之。
2. 實驗首次證明人類橈動脈平滑肌細胞上有 AE、CHE 排鹼蛋白,且分別佔了48%以及26%的總排鹼能力。
3. 尿壓素改變人類橈動脈平滑肌細胞 pHi,可能是透過活化 AE 或是抑制 NHS 所產生的結果。
4. 尿壓素可以增加人類橈動脈平滑肌細胞上 NHE、CHE 的活性。
5. 瓣膜受損、心衰竭、冠狀動脈須繞道等心臟疾病相關之病人血中尿壓素濃度比正常人高出許多。
Background
Changing intracellular pH (pHi) influences many cellular functions, such as enzyme activities and cell volume. The pHi regulators include, Na+-H+ exchanger (NHE), Na+-HCO3- symportor (NHS), Cl--OH- exchanger (CHE), Lactate--H+ symportor and Cl--HCO3- exchanger (AE) in different mammalian cells. However, acid loaders of pHi regulators in human radial artery smooth muscle cells (HRASMCs) have not been characterized. Human radial artery is also an important material in coronary artery bypass graft surgery. Other studies showed that human urotensin-II (U-II) is a powerful vasoconstrictor in isolated blood vessels, even more potent than endothelin-1, angiotensin II and noradrenaline. Our present study was to i) examine the possible pHi acid loaders; ii) investigate the effect of human U-II on pHi regulators in HRASMCs; iii) measure serum U-II concentration in different heart disease patients.
Materials and Methods
Human radial arteries were obtained from patients undergoing bypass grafting. Cultured HRASMCs were derived from the segments of human radial artery, which were cut open longitudinally prior to denudation of endothelium and dissection of small squares to be placed into culture dish and bath with HAM’s F12K medium. Changes of pHi were detected by microspectrofluorimetry method with a pH-sensitive fluorescent dye, BCECF-AM. U-II serum concentration will be quantified by U-II ELISA kit.
Results
1. We have successfully cultured single cells from tissue of human radial artery with identification of antibody of HRASMCs, as well as specificity of morphology.
2. In HEPES buffered Tyrode solution, 3 pM~100 nM U-II exert no effects on resting pHi.
3. In CO2/HCO3- buffered Tyrode solution, 10、30 and 100 nM U-II decrease resting pHi (~ - 0.06 pH unit; P<0.05, n=7) in a way of non-concentration dependent.
4. In HEPES buffered Tyrode solution, 3、10、30、100、300 and 1000 pM U-II increase NHE activity (+20%; +32%; +55%; +86%; +89% and +91%, respectively, P<0.05. n=5) in a way of concentration dependently. However, higher concentration of U-II (10~100 nM) increase NHE activity about 60% (P<0.05, n=5). In other words, U-II show bi-phasic effect on NHE.
5. We have demonstrated that two Cl--dependent acid loaders, most likely are (CHE) and (AE), are functionally coexisted in the HRASMCs. Also CHE and AE play different extent (26% and 48%, respectively) on acid loading following induced intracellular alkalosis in CO2/HCO3--buffered Tyrode solution.
6. In HEPES buffered Tyrode solution, (3、10、30、100 nM) U-II increase CHE activity (+24%、+32%、+36%、+56% and +19%, respectively, P<0.05, n=5) in a way of concentration dependent.
7. Serum U-II concentration in patients group (985 pM) are much higher than healthy control group (210 pM). Especially in heart failure group (2291 pM).
Conclusions
We have demonstrated for the first time that two acid loaders (AE, CHE) are coexisted in the HRASMCs, and responsible for recovery from intracellules alkalosis in different extent (48% and 26%). U-II increases both NHE and CHE activity, but, decreases resting pHi. Moreover we found that the serum concentration of U-II in patients of some cardiovascular disease (heart failure、coronary arteries by pass graft and valve disease) are much higher than that of healthy control.
第一章、 緒論 1
第一節 細胞內酸鹼恆定的重要性 1
壹、 主動或被動運輸細胞內氫離子 2
貳、 pHi regulator 的證實 3
參、 排酸蛋白 Na+-H+ exchanger(NHE) 4
肆、 排酸蛋白 Na+-HCO3- symportor(NHS) 6
伍、 Na+-H+ exchanger 及 Na+-HCO3- symportor 排酸機轉的互動 7
陸、 排鹼蛋白 Cl--OH- exchanger(CHE) 8
柒、 排鹼蛋白 Cl--HCO3- exchanger(AE) 9
第二節 pHi 恆定對血管功能的影響 9
壹、 pH值對血管收縮力的影響 9
貳、 血管平滑肌細胞內鈣離子及酸鹼度之間的相關性 10
第三節 尿壓素(Urotensin-II;U-II) 11
壹、 尿壓素對血管的影響 12
貳、 尿壓素與尿壓素受體系統 14
參、 尿壓素與心血管疾病 15
第四節 本實驗研究目的 17
第二章、 實驗材料與方法 18
第一節 實驗材料 18
壹、 人類橈動脈平滑肌細胞 (human radial artery smooth muscle cells, HRASMCs) 18
貳、 人類全血檢體 (human whole blood) 18
第二節 藥品與溶液 18
壹、 藥品 18
貳、 溶液 20
第三節 實驗裝置部分 22
壹、 細胞培養及鑑定實驗裝置 22
貳、 螢光顯微技術裝置 22
參、 Enzyme-Link ImmunoSorbent Assay(ELISA)實驗裝置 23
第四節 實驗方法 23
壹、 實驗細胞之架置 23
貳、 人類橈動脈平滑肌細胞(HRASMCs)之培養與鑑定 23
參、 顯微螢光技術(Microspectrofluorimetry) 26
肆、 pHi校正 28
伍、 NH4Cl pre-pulse技術 30
陸、 Sodium acetate pre-pulse技術 31
柒、 L-lactate pre-pulse 技術 33
捌、 Enzyme-Link ImmunoSorbent Assay(ELISA) 33
玖、 統計方法 35
第三章、 實驗結果 36
第一節 人類橈動脈平滑肌細胞之鑑定 37
第二節 Urotensin-II 對人類橈動脈平滑肌的 resting pHi 影響 38
壹、 HEPES-buffered Tyrode solution 灌流實驗 38
貳、 CO2/HCO3--buffered Tyrode solution灌流實驗 39
第三節 橈動脈平滑肌細胞之酸鹼調控機轉 39
壹、 HEPES-buffered Tyrode solution灌流實驗 40
貳、 CO2/HCO3--buffered Tyrode solution灌流實驗 41
第四節 Urotensin-II 對於細胞內酸鹼調控蛋白的影響 42
壹、 HEPES-buffered Tyrode solution灌流實驗 42
貳、 Sodium citrate solution灌流實驗 44
第五節 檢測血清中 Urotensin-II 濃度 45
第四章、 討論 47
第一節 人類橈動脈平滑肌細胞之酸鹼調控機轉 47
第二節 Urotensin-II 對人類橈動脈平滑肌細胞的影響 48
第三節 Urotensin-II 對人類橈動脈平滑肌細胞排酸排鹼蛋白影響 48
第四節 Urotensin-II 對人類橈動脈平滑肌細胞 Lactate--H+ symportor 功能性的影響 50
第五節 心臟外科病人血中的 Urotensin-II 濃度與疾病的相關 50
第五章、 結論 52
字母縮寫表 79
參考文獻 80
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