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標題: | 基質金屬蛋白酶影響缺血後心肌细胞外基質降解以及影響動靜脈瘻管血管重塑的研究 Matrix Metalloproteinases in Post-Ischemic Heart and in Arteriovenous Fistula |
作者: | Chih-Yang Chan 詹志洋 |
指導教授: | 陳朝峰 |
關鍵字: | 重塑,紅細胞生成素,缺血/再灌注,動靜脈瘻,管,組織型金屬蛋白酶,抑制劑,膠原蛋白,基質金屬蛋白酶, Remodeling,erythropoietin, EPO,ischemia/reperfusion, IR,arteriovenous fistula, AVF,matrix metalloproteinase, MMP,extracelular signal-regulated kinase, ERK,tissue inhibitor of metalloproeinase, TIMP,collagen, |
出版年 : | 2007 |
學位: | 博士 |
摘要: | 基質金屬蛋白酶 (matrix metalloproteinases, MMPs) 能特異性分解细胞外基質 (extracellular matrix, ECM),對心臟血管组織的蛋白沉積量和组織结構的重塑 (remodeling) 具有重要作用。MMPs 的調控異常也曾報告過與許多血管疾病有關聯。
靜脈管腔膨脹和管壁增厚是臨床上常用為血管通路的動靜脈瘻管 (arteriovenous fistula, AVF) 成熟過程的一部分,也就是所謂的血管重塑。但是影響 AVF 重塑的機制以及它是否受到 MMPs 的影響依然是未知。於是我們在大鼠實驗研究 MMPs 是否在 AVF中加強血管重塑扮演一重要角色。結果證實了我們的假說,高血流率在AVF 靜脈段影響MMPs 表現量,造成AVF 的重塑或成熟性。並且這種血管重塑與基質膠原蛋白的退化有關,膠原蛋白I/III 比率因而上昇。 過去研究顯示心肌缺血後會調高 MMPs,並且促進心肌細胞凋亡,引起梗塞的心臟的心室擴張,並且造成隨後心臟功能不良。雖然過去研究已知基因重組人類紅血球生成素 (recombinant human erythropoetin, rhEpo, EPO) 可以保護心肌免受缺血-再灌流傷害 (ischemia-reperfusion, IR),但它是否影響 ECM 降解退化還不為人所知。因此,我們研究了 MMPs 在心臟缺血後的角色,並且檢查由EPO觸發 Janus kinase 2-Extracelular kinase (Jak2-ERK) 調控信號途徑的作用,是否影響 MMPs 的表現和膠原蛋白 (collagen) 的量。這些觀察顯示,EPO 可以顯著降低心肌IR 傷害後ECM 降解退化,這也許是保護心肌免受細胞死亡的依據。而且 Jak2-ERK 的活化也許在這個過程中是一個重要信號途徑。 在心血管疾病的基礎科學和臨床研究上,MMPs 持續代表一個扣人心弦的焦點。我們的觀察顯示有能力分解基質的MMPs 不論在EPO 的心肌保護作用和在周邊AVF 的血管重塑上都扮演重要角色。能夠調控MMP 作用的治療藥物也許很快被開發,有可能未來將改善心血管的治療。 Matrix metalloproteinases (MMPs) are extracellular matrix (ECM)–modifying enzymes that are important in the degradation of ECM components and in many physiologic and pathologic cardiovascular processes. Dysregulation of MMPs activity has also been associated with various vascular diseases. Venous dilatation and wall thickening are part of the maturation of a surgically created arteriovenous fistula (AVF) commonly used for vascular access. However, the underlying mechanism of AVF remodeling and whether it affected by the MMPs remains unknown. We therefore studied if matrix remodeling MMPs may contribute to experimental AVF maturation in rats. The results confirmed our hypothesis that a high blood flow rate in the fistula vein affects the expression of MMPs, resulting in the remodeling or maturation of the AVF. Remodeling is associated with degradation of collagen, with an increase in the collagen I/III ratio. MMPs are upregulated by myocardial ischemia, and this facilitates the apoptosis of cardiomyocytes and contributes to the subsequent cardiac dysfunction and to ventricular dilation of the infarcted hearts. Although recombinant human erythropoietin (rhEpo, EPO) protects the myocardium from ischemia-reperfusion injury (IR), but whether it affects ECM degradation is not known. For this reason, we studied MMPs in the post-ischemic hearts and examined the effect of the Janus kinase 2-Extracelular signal-regulated kinase (Jak2-ERK) pathway, which is triggered by EPO, on the expression of MMPs and collagen in post-ischemic hearts. These observations show that EPO attenuates ECM degradation following IR and this may be the basis of the protection from cell death. Jak2-ERK phosphorylation may be an important signal in this process. MMPs continue to represent an exciting focus for basic science and clinical investigation in cardiovascular disease. Our observations show that matrix remodeling MMPs play roles both in EPO myocardial protection and in peripheral AVF remodeling. It is possible that therapeutic modulation of MMP function may soon be developed and will one day change the practice of cardiovascular treatment. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/27930 |
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