- 期刊
Fenofibrate Represses Matrix Metalloproteinase-2 in Endothelial Cells Fenofibrate Represses Matrix
Fenofibrate抑制內皮細胞基質金屬蛋白－2(Matrix Metalloproteinase-2)之表現
摘要
Fenofibrate已廣泛使用於心血管疾病病患之高酯血症。現今之研究發現，fenofibrate經由活化過氧化體增生活化接受體α(Peroxisome Proliferator Activated Receptor type alpha, PPARα)，改變酯質代謝而達到血管保護作用，而多數証據亦證實fenofibrate經由多效作用(Pleiotropic effect)對血管造成保護作用。以往研究顯示，血管內皮細胞失調對於動脈硬化之成因扮演極重要之角色，本實驗探討fenofibrate對於血管內皮細胞保護作用之機轉。血管內皮細胞經fenofibrate處理後可抑制基質金屬蛋白－2之表現、內皮細胞基質金屬蛋白－2之分泌與活性。Fenofibrate可經由磷酸化Ser1177造成活化，而經由L-NAME抑制內皮型一氧化氮合成(eNOS)可減緩fenofibrate造成抑制基質金屬蛋白－2之表現。本實驗證實了fenofibrate抑制基質金屬蛋白－2需要一氧化氮(NO)之參與。總之，本研究發現fenofibrate可活化eNOS，增加一氧化氮生物利用度，進而抑制基質金屬蛋白－2之表現。本研究提供fenofibrate造成血管保護作用之機轉，期望能衍伸爲臨床之應用。
關鍵字
無資料並列摘要
Fenofibrate is a widely used to ameliorate hyperlipidemia and/or hypercholesterolemia in patients at risk of cardiovascular disease. To date, most of its favorable effects have been attributed to its activation of peroxisome proliferator activated receptor alpha (PPARα), which alters lipid metabolism, contributing to an improved lipid profile. Lines of evidence suggest pleotrophic effects of fenofibrate in cardiovascular system. Given that endothelium is the frontier of vasculature and its dysfunction is prelude of various vascular disorders, e.g. atherosclerosis and arterial stiffening, we investigated the effect of fenofibrate in human endothelial cell (EC) line (Eahy926). Fenofibrate treatment in ECs repressed matrix metalloproteinase-2 (MMP-2) expression in ECs as well as endothelial MMP-2 secretion, associated with decreased MMP-2 activity. In parallel, fenofibrate activated endothelial nitric oxide synthase (eNOS), demonstrated by Ser1177 phosphorylation. Inhibition of eNOS by L-NAME attenuated fenofibratesuppressed MMP-2, indicating fenofibrate inhibits MMP-2 requires eNOS-derived NO. Collectively, these findings suggest that fenofibrate activates eNOS and increases NO-bioavailability, which in turn suppresses overactivation of MMP-2, contributing to maintenance of endothelial homeostasis. The present study provides a molecular rationale in which fenofibrate exerts vascular protective effects, facilitating the clinical application of its derived medicine.