Expression of Hypoxia Inducible Factor–1α, Macrophage Migration Inhibition Factor, Matrix Metalloproteinase–2 and −9, and Their Inhibitors in Hemodialysis Grafts and Arteriovenous Fistulas

Abstract

It is well recognized that arteriovenous fistulas (AVFs) used for hemodialysis access have better primary patency rates with less restenosis than polytetrafluoroethylene (PTFE) grafts; however, the mechanism responsible for this is not known. Recent data suggest that hypoxia inducible factor-1 alpha (HIF-1 alpha) is associated with vascular restenosis, possibly through mechanisms that increase the production of macrophage migration inhibition factor (MIF), matrix metalloproteinase-2 (MMP-2) and MMP-9, and their inhibitors (tissue inhibitor of MMPs; TIMP). The present study tested the hypothesis that there are differences in the expression patterns of HIF-1 alpha, MIF, MMP-2, MMP-9, and TIMPs in specimens removed from patients with AVFs and PTFE grafts. Whole-vessel tissue samples were obtained from the vein distal to the vein-to-PTFE graft anastomosis and the proximal outflow vein (within 6 cm of the arteriovenous anastomosis) of AVFs from 17 patients who required a surgical revision for thrombosis and stenosis. Nonstenotic veins of four patients undergoing hemodialysis vascular access placement were used as controls. PTFE grafts (n = 6), AVFs (n = 6), and control samples (n = 3) underwent Western blot analysis and zymography. A separate group of five patients with PTFE hemodialysis grafts and one control subject were used for immunohistochemical analysis. Specimens from patients with PTFE grafts had significantly higher expression of HIF-1 alpha (P = .03), MIF (P = .02), TIMP-1 (P = .0006), pro-MMP-2 (P = .02), and pro-MMP-9 (P = .046) compared with control veins. The expression of only pro-MMP-9 was significantly higher in AVFs compared with control samples (P = .004). There was a significant increase in the expression of MIF (P = .007) and TIMP-1 (P < .0001) in PTFE graft specimens compared with AVFs. MIF and TIMP-1 were localized to the adventitia of the vein distal to the vein-to-PTFE graft anastomosis. There were major differences in the expression patterns of hypoxia (ie, HIF-1 alpha) and proteins regulated by HIF-1?, including MIF, pro-MMP-2, pro-MMP-9, and TIMP-1, in specimens removed from patients with PTFE grafts and AVFs. Understanding the role of HIF-1 alpha and these proteins in hemodialysis access failure can help improve outcomes.