皮質酮-鹽(deoxycorticosterone acetate-salt, DOCA/salt)高血壓老鼠是研究腎性高血壓常使用的一種實驗動物模式，其血中發現內皮細胞素(endothelin-1,ET-1)的含量會增加，而且，心血管組織有肥大增厚現象(hypertrophy)。可是，DOCA對內皮細胞表現ET-1的作用則尚不清楚。本論文使用源自人類臍靜脈血管之內皮細胞株(human umbilical vein endothelial cell, HUVEC)，經DOCA處理後，研究HUVEC細胞內ET-1及一氧化氮合成 (endothelial nitric oxide synthase, eNOS) 基因調控的變化。北方點墨法(Northern blotting)發現DOCA可增加HUVEC細胞ET-1 的mRNA表現量，然而，經DOCA處理的HUVEC的eNOS mRNA量卻明顯的減少。ET-1 mRNA增加的現象及eNOS mRNA減少的現象，在加入礦皮醇受體(mineralocorticoid receptor, MR)拮抗劑的spironolactone (SP)或糖皮醇受體(glucocorticoid receptor, GR) 拮抗劑的mifepristone (RU486)後，會被顯著的抑制。由放射免疫法(Radioimmunoassay, RIA) 分析得知DOCA有促進的ET-1合成及分泌的作用，而且會受到RU486及SP的抑制。另外，西方點墨法(Western blotting)也測得DOCA處理後之HUVEC的eNOS的蛋白量減少；並受到SP及RU486的抑制。而且，以放射線標定之eNOS受質L-[3H] arginine為受質，檢測HUVEC細胞eNOS的酵素的活性。結果顯示，DOCA會減低eNOS的活性；這項作用也會被RU486及SP抑制。
近年來，過氧小體增生活化受體(Peroxisome proliferator-activated receptors, PPARs)被認為與血管功能的調控有密切的關係，當PPARs受到ligand的刺激後，會抑制ET-1的分泌，而且可以降低血壓及其危險因子；存在於內皮細胞的有alpha (PPARa)及gamma (PPARg)兩種亞型。由反轉錄-聚合連鎖反應(reverse transcription-polymerase chain reaction, RT-PCR) 的結果顯示，DOCA可以刺激PPARg的基因表現；這種作用可被RU486 及SP所抑制。此外，ET-1 B型受體(ETB receptor)阻斷劑的BQ-788亦可阻斷DOCA對PPARg的作用，protein kinase C (PKC)阻斷劑的chelerythrine 也會抑制DOCA所刺激的PPARg表現。因此，DOCA除了影響ET-1或eNOS的基因以外，亦可刺激PPARg的表現。
研究結果顯示，DOCA對HUVEC基因表現的調控，可能經由類固醇受體(steroid receptor)的途徑，使細胞的ET-1基因表現增加；同時，eNOS基因表現也會受到抑制。另一方面，DOCA也會使PPARg基因的表現增加，這項作用可能與活化ETB受體有關。綜合言之，由皮質酮-鹽所導致的高血壓，皮質酮本身即可刺激血管內皮細胞的ET-1基因表現，並且，抑制了eNOS的基因表現，進而刺激血管收縮，產生高血壓的病變；而PPARg基因的調控，可能直接或間接的影響皮質酮-鹽高血壓的發生。

Increase of endothelin-1 (ET-1) peptide with hypertrophy in cardiovascular system has been characterized in the deoxycorticosterone acetate-salt (DOCA/salt) hypertensive rats. However, the direct effects of DOCA on the expression of ET-1 in endothelial cells remained obscure. In this study, the gene expression and protein level of ET-1 and endothelial nitric oxide synthase (eNOS) in DOCA treated human umbilical vein endothelial cell line (HUVEC) were investigated. Also, the amount of secreted ET-1 and enzyme activity of eNOS were studied.
Northern blotting analysis showed that mRNA level of ET-1 was elevated in the DOCA treated HUVEC while level of eNOS mRNA was decreased. The selective antagonist of mineralocorticoid receptors (MR) or glucocorticoid receptors (GR), either spironolactone (SP) or mifepristone (RU486), antagonized the effects of DOCA regarding the increase of ET-1 mRNA and the decrease of eNOS mRNA. Intracellular endothelins peptide determined by radioimmunoassay (RIA) showed that increase of ET-1 peptide in DOCA treated HUVEC was inhibited by SP or by RU486. Western blotting analysis showed the decrease of eNOS protein by DOCA that can be reversed by SP or RU486 pre-treatment. In addition, the increase of secreted ET-1 was also antagonized with SP or RU486. In the activity assay, [3H] labeled L-arginine was used to determine the enzyme activity of eNOS. The decreased of eNOS activity was observed in DOCA-treated HUVEC and reversed by SP and RU486 treatment.
Gene expression in the reverse transcription-polymerase chain reaction (RT-PCR) of peroxisome proliferator activated receptors gamma (PPARg) was stimulated in the DOCA treated HUVEC that can be antagonized by RU486, SP, BQ788 (antagonist of ETB receptor) and chelerythrine (protein kinase C (PKC) inhibitor). Thus, DOCA has an effect on the expression of PPARg.
From the obtained results, the present study indicated that DOCA might modulate the ET-1 and eNOS gene expression in the HUVEC via steroid receptor. Also, PPARg gene was increased by DOCA in HUVEC.

目 錄
中文摘要1
英文摘要3
誌謝
第一章 緒論5
1-1. 血壓概論5
1-2. 皮質酮-鹽 (deoxycorticosterone acetate-
salt, DOCA-salt) 高血壓7
1-3. 內皮細胞素 (endothelins, ETs)8
1-4. 一氧化氮合成 (nitric oxide synthase, NOS)11
1-5. 過氧小體增生活化受體Peroxisome
proliferator-activated receptors (PPARs)12
1-6.研究目標14
縮寫表16
第二章實驗設計與研究方法17
2-1. 內皮細胞培養18
2-2. 細胞存活率計數18
2-3. 由轉型之細菌體內純化cDNA (Purification
of cDNA from transformed bacteria )19
2-4. 北方點墨法 (Northern blotting)23
2-5. 西方點墨分析法26
2-6. 一氧化氮合成活性檢測28
2-7. 放射免疫分析法(Radioimmunoassay, RIA)29
2-8. 反轉錄-聚合連鎖反應(reverse transcription-
polymerase chain reaction, RT-PCR)29
2-9. 統計分析30
第三章實驗藥品及儀器31
3-1. 實驗試劑32
3-2. 實驗器材33
第四章結果34
4-1. 細胞形態及存活率的改變35
4-2. 皮質酮處理內皮細胞，在不同作用時間下
的內皮細胞素基因的調控35
4-3. 礦皮醇受體拮抗劑spironolactone (SP)
及糖皮醇受體拮抗劑mifepristone (RU486)
對DOCA刺激ET-1 表現的影響36
4-4. 經DOCA 處理不同時間的HUVEC細胞，
內皮細胞一氧化氮合成基因的調控37
4-5. ET-1 peptide對於eNOS基因表現的影響40
4-6. HUVEC細胞之PPARg 基因的調控41
第五章討論44
結論52
參考文獻53
附圖68
附表110

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