Effect of Chymase Inhibition on the Arteriovenous Fistula Stenosis in Dogs

Abstract

It was hypothesized that chymase may participate in hemodialysis vascular access dysfunction, as chymase has been known to be an effective enzyme in the conversion of angiotensin I (Ang I) to Ang II and in the latent TGF-␤1 to the active form. An arteriovenous (AV) fistula was created between the brachial artery and vein in dogs. In the AV anastomosis, when the walls of the venous and arterial sides were compared, the eccentric neointimal formation was most evident in the venous wall. Compared with the venous side downstream of the AV anastomosis, a severe neointimal hyperplasia was found in the venous side upstream of the AV anastomosis (intima/media, 153 ؎ 25%). The chymase-and TGF-␤-positive mast cells were markedly accumulated in the proliferous neointima and media. In association with the reduction of chymase expression, a marked decrease in Ang II-, AT 1 receptor-, and TGF-␤-positive areas was achieved by NK3201 (a chymase inhibitor) treatment, and the neointima formation (intima/media: region A, 53 ؎ 9%, P < 0.001; region B, 54 ؎ 14%, P < 0.001) was also significantly suppressed in this group. Although lisinopril treatment also provided some beneficial effects with regard to the prevention of neointimal formation, the degree was less than that seen with chymase inhibition. These findings indicate that mast cell-derived chymase plays an essential role in the pathogenesis of the AV fistula access failure and that chymase inhibition may be a therapeutic target for the treatment of hemodialysis vascular access dysfunction in clinic settings.

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“…1C. Once these sections (3 μm in thickness) were obtained, the following general histologic and immunohistologic examinations were performed, as described previously (3,6,7).…”

Anti-Atherosclerotic Effects of Dihomo-.GAMMA.-Linolenic Acid in ApoE-Deficient Mice

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