研究生: |
萬瑋琳 Wan, Wei-Lin |
---|---|
論文名稱: |
探討microRNA-10a在剪力誘導血管內皮細胞發炎過程中所扮演的角色 The role of microRNA-10a in modulating shear-induced inflammatory response in vascular endothelial cells |
指導教授: |
裘正健
Chiu, Jeng-Jiann |
口試委員: |
陳令儀
張文祥 |
學位類別: |
碩士 Master |
系所名稱: |
工學院 - 生物醫學工程研究所 Institute of Biomedical Engineering |
論文出版年: | 2014 |
畢業學年度: | 102 |
語文別: | 中文 |
論文頁數: | 58 |
中文關鍵詞: | 動脈粥狀硬化 、流體剪應力 、發炎反應 、內皮細胞 、微型核醣核酸 、機械力訊息傳導 、視黃酸受體 |
外文關鍵詞: | atherosclerosis, fluid shear stress, inflammatory response, endothelial cell, microRNA, mechanotransduction, retinoic acid receptor |
相關次數: | 點閱:2 下載:0 |
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動脈粥狀硬化 (atherosclerosis) 為誘發心血管疾病的主因,好發於血管彎曲和分歧處附近,此處流體剪應力 (fluid shear stress) 主要為振盪型剪應力 (oscillatory shear stress),容易引起內皮細胞產生發炎、增生、氧化等反應;另一種流體剪應力為脈衝型剪應力 (pulsatile shear stress),作用於不易發生動脈硬化的區域,能抑制內皮細胞產生病變。因此血液流動所產生的流體剪應力被認為是調控血管壁發炎反應及動脈粥狀硬化生成的重要因子。最近研究指出,miRNA-10a具有抗發炎效用,在好發動脈粥狀硬化區域表現量較低,但不同流體剪應力調控miRNA-10a的相關訊息傳導機制尚未被闡明。本研究透過體外流體實驗證實振盪型剪應力 (0.5 ± 4 dynes/cm2) 與脈衝型剪應力 (12 ± 4 dynes/cm2) 分別具有抑制和提升內皮細胞miRNA-10a表現的能力,受流體剪應力調控的miRNA-10a將進一步影響下游分子第六型GATA (GATA-6) 及血管細胞黏著分子-1 (VCAM-1) 的表現,調控細胞內部的發炎反應。轉染視黃酸受體-α (RARα) 與視黃醇X受體-α (RXRα) 的專一性siRNA至內皮細胞,可以分別完全抑制與部份抑制脈衝型剪應力所誘導的miRNA-10a表現。在動物實驗中,ApoE缺損 (ApoE-/-) 的小鼠餵食高膽固醇飼料的血管會展現動脈硬化損傷的型態。給予小鼠PreR-10a將能增加血管內皮細胞miRNA-10a的表現,並避免動脈硬化損傷的形成。這些結果顯示視黃酸受體-α扮演主要調控miRNA-10a的角色,可與視黃醇X受體-α建構複合體,調控不同流體剪應力對miRNA-10a表現的影響,進而調控內皮細胞發炎反應及血管動脈硬化生成。
The major cause of cardiovascular disease is atherosclerosis, which develops preferentially at arterial branches and curvatures. The fluid shear stress (FSS) in these regions is oscillatory shear stress (OSS). OSS has been shown to play important roles in modulating various responses involved in endothelial cell (EC) dysfunction. The other kind of fluid shear stress is pulsatile shear stress (PSS), which generally occurs in areas spared from atherosclerotic lesions. Therefore, FSS is considered as an important factor to modulate inflammation and atherosclerosis in vascular wall. Recently, miRNA-10a has been identified as an anti-inflammatory molecule in athero-susceptible regions in vivo. However, whether miRNA-10a can be regulated by different FSS patterns and the detailed mechanisms involved in this mechanotransduction remain unclear. In the present study, we investigated the role of miRNA-10a in regulating inflammatory responses of ECs to different FSS patterns. Application of OSS (0.5 ± 4 dynes/cm2) and PSS (12 ± 4 dynes/cm2) to HUVECs can sustainably down-regulate and up-regulate miRNA-10a expression, respectively. This flow-regulated miRNA-10a expression could consequently regulate the expression of its directed target GATA-6 and downstream vascular cell adhesion molecule-1 (VCAM-1). Transfecting ECs with RARα-specific siRNA could totally inhibit PSS-induced miRNA-10a expression, but RXRα-specific siRNA could only partially inhibit this response. The vascular of ApoE-/- mice fed with high-cholesterol diet express atherosclerotic lesions formation. Administration of PreR-10a can enhance miRNA-10a expression in the vascular endothelial cell and prevent atherosclerotic lesions formation. These results suggest that RARα/RXRα could constitute regulatory complex to switch miRNA-10a expression in response to different FSS patterns in regulating inflammatory response and atherosclerosis formation.
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