黃芩苷元對內皮細胞血管新生生物效應機轉之探討;Bioeffect mechanism of Baicalein on Angiogenesis of Endothelial Cells

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Title:	黃芩苷元對內皮細胞血管新生生物效應機轉之探討;Bioeffect mechanism of Baicalein on Angiogenesis of Endothelial Cells
Authors:	謝昀志;Yun-Chih Hsieh
Contributors:	中國醫藥大學：中國藥學研究所博士班
Keywords:	血管新生;黃芩苷;元;Integrin;Yeast two-hybrid;siRNA;expression;angiogenesis;baicalein
Date:	2007-07-05
Issue Date:	2009-08-11 10:25:13 (UTC+8)
Abstract:	心臟血管病變以及癌症是人類重要的死亡疾病，先前的醫藥研究人員都積極的在研發能夠有效的對抗此類疾病的方法及方針，應用新的血管新生的模式來治療心血管疾病及尋找對抗癌症血管新生的藥物是我們從事中藥研究的目的，黃芩苷元（baicalein）為本研究所探討的藥物，可以抑制老鼠心臟內皮細胞之生長，降低細胞週期激酶之活性，使內皮細胞生長減緩甚至停滯，表示黃芩苷元可能對於內皮細胞的血管新生有很大的影響。在實驗中我們發現黃芩苷元在in vivo和in vitro實驗中造成微細血管的形成，經由抑制TIMPs的表現影響MMPs分子進而改變與ECM分子之間的作用，促進內皮細胞的侵入，此外我們發現黃芩苷元也可以調控integrin α5β1、integrin αvβ3和vinculin的表現，促使actin fiber的重組與增加局部黏附分子的形成和黏附，使得內皮細胞爬行降低。我們從中藥分子的角度探討在存在黃芩苷元的狀態下，的確可以抑制血管新生的作用，但是前處理黃芩苷元後，反而造成血管新生能力的增加，這代表黃芩苷元可能是血管新生的inducer與potentiator，可作為血管新生的angiostatic也可作為angiogenic。進一步我們學習了對ABLIM1、TMOD1、CYR61、ENO1、MBP1、PLSCR1、SLR417和RAI3基因做基本的Yeast two-hybrid system與expression system的構築，並架構了MAP2K1、MAP2K2、MAPK1、MAPK3、MAPK8、MAPK9、MAPK14、RARα、RARβ、RARγ、RXRα、RXRβ、RXRγ、ABLIM1、ENO1、TMOD1、RAI3和Fos的U6 promoter與pSIREN system的siRNA，期望利用人工合成基因轉殖對細胞基因的增加與減少，探討中藥藥物對於單一基因與蛋白直接的影響，並尋找與重組基因蛋白之間相互作用的蛋白，進一步瞭解中藥藥物在這些相關基因與蛋白分子間所扮演的角色，期望能從中藥藥物對於心血管細胞組織與癌症相關基因中尋找有用的中藥藥物。 Baicalein, a flavonoid present in the root of Scutellaria baicalensis GEORGI, has been reported to inhibit proliferation in rat heart endothelial cells. In this study, the effect of baicalein on cell angiogenesis was examined in vivo and in vitro experiment to observe the bioeffect mechanism in endothelial cells. We found baicalein inhibited angiogenesis well but pretreatment with baicalein significantly induced the formation of tube-like structures both in vitro and in vivo. The activation of invasion was increased by pretreatment with baicalein that change endothelial cells and ECM interaction. Baicalein-mediated MMPs activity and decreased TIMPs protein levels and mRNA levels by promote of gelatinolytic activity. Thus, our observations demonstrated that baicalein drastically inhibited the migration and enhanced the adhesion of rat heart endothelial cells, possibly by up-regulation of the integrin α5β1, integrin αvβ3 and vinculin, and promotion of actin reorganization and focal adhesion contact formation. We have provided a evidence to indicate baicalein control angiogenesis by up-regulation of integrins on the surface of endothelial cells. Baicalein is an angiogenesis promoter and potentiator in vivo, may use as an angiostatic and angiogenic. Furthermore, we constructed ABLIM1, TMOD1, CYR61, ENO1, MBP1, PLSCR1, SLR417, and RAI3 expression and Yeast-Two hybrid system plasmids. We also constructed MAP2K1, MAP2K2, MAPK1, MAPK3, MAPK8, MAPK9, MAPK14, RARα, RARβ, RARγ, RXRα, RXRβ, RXRγ, ABLIM1, ENO1, TMOD1, RAI3, and Fos siRNA plasmids in plasmid U6 and pSIREN system witch promoted by U6 promoter. We proposed to observation specific gene overexpression and knocksown in cell. Using these plasmids to regulate medical molecules involved in protein-protein interaction between cells and tissue expression. Thus, we explain to find new therapeutically mechanisms in vascular disorder and cancer angiogenesis.
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