Effect of chymase inhibition on the arteriovenous fistula stenosis in dogs.
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-beta1 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-beta-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-beta-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.
Jin
Denan
D
Department of Pharmacology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan. pha012@art.osaka-med.ac.jp
Ueda
Haruhiko
H
Takai
Shinji
S
Okamoto
Yukiko
Y
Muramatsu
Michiko
M
Sakaguchi
Masato
M
Shibahara
Nobuhisa
N
Katsuoka
Yoji
Y
Miyazaki
Mizuo
M
D000081:Acetamides / Q000494:pharmacology*; D000804:Angiotensin II / Q000037:antagonists & inhibitors; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D001916:Brachial Artery / Q000601:surgery; D053818:Chymases; D003251:Constriction, Pathologic; D004285:Dogs; D006965:Hyperplasia; D008407:Mast Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D012697:Serine Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017540:Tunica Media / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014680:Veins / Q000473:pathology* / Q000601:surgery
D000081:Acetamides; D047228:Angiotensin II Type 1 Receptor Blockers; C437945:NK3201; D011480:Protease Inhibitors; D011743:Pyrimidines; D044140:Receptor, Angiotensin, Type 1; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D012697:Serine Endopeptidases; D053818:Chymases