ISOSTEVIOL對ANGIOTENSIN-II所誘發大動脈平滑肌細胞增生的作用及機轉

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题名:	ISOSTEVIOL對ANGIOTENSIN-II所誘發大動脈平滑肌細胞增生的作用及機轉
作者:	黃家樂(WONG KAR-LOK);(鄭志鴻);吳世銓
贡献者:	醫學院醫學系學士班麻醉學科;中國附醫麻醉部
关键词:	Endothelin-1;Isosteviol;Angiotensin II;Smooth muscle cells;Reactive oxygen species
日期:	2007-07-31
上传时间:	2009-09-01 16:19:00 (UTC+8)
摘要:	近來實驗發現；內皮素 (angiotensin II;Ang II)可增加心臟細胞內蛋白質的增生及beta-肌凝蛋白重鍊(beta-myosin heavy chain)的基因表現(Wong KL et al 2005)導致心臟肥大。而此種作用與細胞內活性氧族群(reactive oxygen species; ROS)有關(Wong KL e t a l 2005)。而Ang-II與ROS 亦為導致很多心臟血管疾病的成因相互有關連(Hahn et al.,1990;Ito et al.,1993; Sung et al.,1994; Rossi et al,1999)。先前的研究已知，甜菊(stevioside)在高血壓老鼠可有效的降低血壓，對高血壓心臟傷害防治方面且亦具anti- hypertrophy(Wong KL et al2005，去年本人國科會的研究，且已在國際醫學會上發表)的效果。它在日本及巴西當作代糖已有二十年之久，並無任何不良反應的報告。Isosteviol為 stevioside的衍生物，乃從Stevia rebaudiana萃取所得。本實驗即以內皮素(endothelin-1)誘發平滑肌肉細胞增生及ET-1peptide分泌及其基因表現(gene expression)的模式來探究isosteviol對於培養中平滑肌肉細胞增生的影響及其分子生物機轉。大白鼠動脈平滑肌細胞先以 isosteviol(1-100μM)培養三十分鐘後，再加入angiotensin II(100nM) 績培養二十四小時，isosteviol 以concentration-dependent的形式抑制了Ang II所增加的新脫氧核糖核酸含量由176%降低至118%(p < 0.05)、Endothelin-1(ET-1)的量則由增加200% 降低至146%(p< 0.05)。而isosteviol(1-100μM)、抗氧化劑N-acetyl-cysteine(10mM)及diphenylene iodonium(DPI; 10 μM)皆可降低由Ang II誘導所昇高的細胞內活性氧化物(p< 0.05)，Isosteviol具有抗平滑肌肉細胞增生的效果也顯現在細胞內Reactive oxygen species (ROS) 的抑制上。而且由Ang II所激發(activate)的ERKphosphorylation 皆被isosteviol(1-100 μM)、抗氧化劑N-acetyl-cysteine(10 mM)及diphenyleneiodonium(DPI; 10 μM)所抑制。這些實驗結果顯示isosteviol 能預防平滑肌肉細胞增生的效果乃來自其抗氧化之效力，本研究乃首次明確地闡釋isosteviol 抗平滑肌肉細胞增生之藥理分子生物學機轉，連同先前對isosteviol具降血壓及預防高血壓而導致之心臟肌肉肥大的療效。本研究以更深入探討i sosteviol 對心臟血管細胞的藥理保護機轉，以期推進作為臨床醫療使用的藥理基礎，未來使用在心血管疾病治療上深具展望。 The effect of the positive transcription elongation factor b (P-TEFb), which is composed of CDK9 and cyclin T1, on the activity of the core protein of Type 2 Dengue virus (DEN2) was investigated. The DEN2 core protein was found to activate the expression of the IL-8 gene. This activation was abolished by the CDK9 inhibitor, 5,6-dichloro-1-b-D-ribofuranosylbenzimidazole (DRB), or the anti-cyclin T1 siRNA, indicating that it was dependent on P-TEFb. Results of chromatin immunoprecipitation assays revealed that the DEN2 core protein bound to the transcriptionally active IL-8 gene promoter. The interaction between P-TEFb and the DEN2 core protein was confirmed by the observation that immunoprecipitation of the DEN2 core protein also precipitated P-TEFb. The effect of the DEN2 core protein on IL-8 gene expression was shown to be due to an enhancement on NF-kappaB activity. This enhancement was also dependent on P-TEFb as inactivation of P-TEFb with DRB abolished the effect. The DEN2 core protein was essential in NF-kappaB enhancement since truncation of the last 27 C-terminal amino acid residues of the DEN2 core protein rendering it unable to enter the nucleus resulted in a complete loss of the enhancement. In addition, truncation of the last 15 C-terminal amino acids of the DEN2 core protein reduced its enhancement effect on NF-kappaB. Taken together, results of this study indicate that the DEN2 core protein and P-TEFb work in concert to enhance the effect of NF-kappaB on IL-8 gene expression. This is the first demonstration that P-TEFb directly involves in virus-induced host gene expression by interacting with a certain viral protein.
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