糖尿病患者的動靜脈?管內血流有顯著的下降。據過去研究，史他汀這類的降血脂藥物有著多效性，除了降血脂外尚具有促進血管內皮細胞功能以及降低發炎反應的效果。本研究探討關於糖尿病患動靜脈?管喪失功能的病理機制，並試驗冠脂妥對糖尿病鼠動的靜脈?管是否具有保護的作用。 在大鼠身上注射單劑鏈佐黴素誘發糖尿病，並將大鼠隨機分為兩組，分別接受口服安慰劑以及冠脂妥(15mg/kg/d)。在誘發糖尿病後一週以手術方式在大鼠之降主動脈及下腔靜脈間製造一動靜脈?管。口服藥物治療期共為兩週（術前及術後各一週）。治療結束後測定?管之動脈端的血流流速、測試血管的等長收縮（Isometric force analysis），檢視週邊血液中內皮前驅細胞（CD34+/KDR+, endothelial progenitor cells）數目及分析?管組織中促發炎因子的表現以及超氧陰離子生成。 在糖尿病鼠血液中，血管內皮前驅細胞數量減少。而冠脂妥治療後可顯著地增加血管內皮前驅細胞的數量。在冠脂妥治療組的糖尿病大鼠，其動靜脈?管隻血流量、流速、血管內皮層舒張功能皆有明顯的改善作用。此外，冠脂妥亦可降低糖尿病鼠?管組織中iNOS以及NADPH oxidase的蛋白表現以及減少超氧陰離子和促發炎因子（TNF-α, IL-1β, IL-6）的生成。 本研究證實了冠脂妥可藉由抑制?管組織中促發炎基因之表現，以及降低超氧陰離子生成，達到改善糖尿病鼠之動靜脈?管的血流。本研究的發現提供臨床上改善糖尿病患者動靜脈?管失效之治療依據，並以口服冠脂妥作為改善糖尿病患者動靜脈?管功能及延長其使用壽命的有效治療方針。 Blood flow in the arteriovenous (AV) fistula is significantly reduced in diabetic patients. Statins are known to mediate pleiotropic effects in vascular endothelium and attenuate inflammatory responses. This study investigates the pathogenesis of AV fistula failure in subjects with diabetes mellitus, and tests the vascular protective effect of rosuvastatin on the fistulous communication of diabetic rats. Diabetes mellitus (DM) was induced in rats by a single injection of streptozotocin. Rats were then randomly assigned to receive placebo or rosuvastatin (15 mg/kg/d) in chow for 2 weeks. One week induction of diabetes, a fistula was created in descending aorta and the adjacent IVC (AC fistula). Blood flow in the aortic and venous segments of fistula was measured. Circulating CD34+/KDR+ endothelial progenitor cells (EPCs) were determined using the flow cytometry. Vascular function of AC fistula was assessed by isometric force testing. The expression of pro-inflammatory genes and generation of superoxide anions in the fistula were examined. Number of EPCs was reduced in diabetic rats, and rosuvastatin significantly increased numbers of circulating EPC. Reduced blood flow and impaired endothelium-dependent relaxation in the AC fistula of animals with diabetes was significantly potentiated following treatment with rosuvastatin. Rosuvastatin also attenuated the expression of iNOS and NADPH oxidase, generation of superoxide anions and proinflammatory cytokines (TNF-, IL-1 and IL-6) in the fistula tissues isolated from diabetic rats.We provide the first evidence demonstrating that rosovastatin improves blood flow and endothelial function of AC fistula in rats with diabetes mellitus by attenuating the activity of pro-inflammatory genes and generation of superoxide anions in the remodeled vasculature. These experimental findings serve as fundamental supportive evidences for conducting clinical testing of the protective effect of HMG-CoA reductase inhibitor (statins) in establishing a durable vascular access for hemodialysis in diabetic patients.
