Roles of chymase in stenosis occurring after polytetrafluoroethylene graft implantations.
Chymase is an important enzyme for the generation of angiotensin (Ang) II and in the activation of transforming growth factor (TGF)-beta1. Therefore, chymase may be involved in the hemodialysis access dysfunction, which is caused by intimal hyperplasia that occurs after polytetrafluoroethylene (PTFE) graft implantations. Bilateral U-shaped PTFE grafts were placed between the femoral vein and artery in dogs. Chymase inhibitor (NK3201, 1 mg/kg per day, p.o.) treatments were initiated 3 days before the operation. After the implantation, the stenosis by neointima proliferation was most frequently observed in the venous side of the PTFE grafts. In the hyperplastic neointima, myofibroblasts were the main cellular components. On the other hand, fibroblasts only occupied cellular components in a much smaller proportion in the neointima. However, these cells seem to be rich in the properties of proliferation and migration. After PTFE graft implantations, extensive accumulations of chymase-positive mast cells were found mainly in the tissue surrounding the grafts. The Ang II- and TGF-beta-positive cells were found in an adjacent section that was in close proximity to the chymase-positive cells. In contrast, the AT(1) receptors, as well as TGF-beta type II receptors, were expressed either in the neointima or in the outside adventitia of the PTFE grafts. Chymase inhibitor treatment resulted in a reduction of chymase, Ang II and TGF-beta1 expression, leading to a significant inhibition of neointimal formation. These findings indicating that an increase of chymase via promoting Ang II and TGF-beta1 generation plays a pivotal role in the neointimal formation after the implantation of PTFE grafts and also suggesting that chymase inhibition may be a new strategy that can be used to prevent PTFE graft dysfunctions in clinical settings.
Jin
Denan
D
Department of Pharmacology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan. pha012@art.osaka-med.ac.jp
Ueda
Haruhiko
H
Takai
Shinji
S
Muramatsu
Michiko
M
Furubayashi
Keiichi
K
Ibaraki
Toshihiko
T
Kishi
Kanta
K
Katsuoka
Yoji
Y
Miyazaki
Mizuo
M
D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D049109:Cell Proliferation / Q000187:drug effects; D053818:Chymases / Q000037:antagonists & inhibitors / Q000502:physiology*; D003251:Constriction, Pathologic / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005263:Femoral Artery / Q000201:enzymology / Q000473:pathology / Q000601:surgery; D005268:Femoral Vein / Q000201:enzymology / Q000473:pathology / Q000601:surgery; D008297:Male; D011138:Polytetrafluoroethylene; D011743:Pyrimidines / Q000494:pharmacology; D017539:Tunica Intima / Q000201:enzymology / Q000473:pathology
D000081:Acetamides; D004791:Enzyme Inhibitors; C437945:NK3201; D011743:Pyrimidines; D011138:Polytetrafluoroethylene; D053818:Chymases