The effects of chymase on matrix metalloproteinase-2 activation in neointimal hyperplasia after balloon injury in dogs.
Chymase is known to generate angiotensin II in the vascular wall. In this study we investigated a novel role for chymase other than angiotensin II production in vascular proliferation after balloon injury. Chymase promoted the migration of vascular smooth muscle cells in the matrix-coated invasion chambers and activated promatrix metalloproteinase-2 obtained from the culture medium of vascular smooth muscle cells. Two weeks after balloon injury, significant neointimal formation was found in dog carotid arteries. After injury, active matrix metalloproteinase-2 was increased in parallel with the augmentation of chymase activity that was seen in the proliferating region of the vascular wall. The oral administration of NK3201 (1 mg/kg per day), a chymase inhibitor, prevented neointimal formation and significantly suppressed both active matrix metalloproteinase-2 and chymase activities 2 weeks after injury. These results suggest that chymase inhibitors can prevent the development of intimal hyperplasia via the inhibition of matrix metalloproteinase-2 activation in balloon-injured arteries.
Kishi
Kanta
K
Department of Pharmacology, Osaka Medical College, Takatsuki, Japan.
Muramatsu
Michiko
M
Jin
Denan
D
Furubayashi
Keiichi
K
Takai
Shinji
S
Tamai
Hiroshi
H
Miyazaki
Mizuo
M
D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D002404:Catheterization; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D053818:Chymases / Q000378:metabolism / Q000494:pharmacology*; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*
D000081:Acetamides; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; C437945:NK3201; D011743:Pyrimidines; D053818:Chymases; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase; D020778:Matrix Metalloproteinase 2