Inhibition of inducible nitric oxide synthase and superoxide production reduces matrix metalloproteinase-9 activity and restores coronary vasomotor function in rat cardiac allografts.
OBJECTIVE
Oxidants such as nitric oxide (NO) and superoxide are involved in coronary endothelial dysfunction, an early event in the process of allograft coronary atherogenesis, possibly by activation of matrix metalloproteinases (MMPs) and extracellular matrix proteins. We investigated the contribution of inducible nitric oxide synthase (iNOS) derived NO and superoxide on (MMP)-9 activity and to changes in coronary vasomotor function in rat cardiac allografts.


RESULTS
An allogenic (Brown Norway to Lewis rats) heterotopic cardiac transplantation model was used to study the effect of continuous treatment with a selective iNOS inhibitor; N-(3-(aminomethyl) benzyl) acetamidine (1400W), and polyethylene glycol conjugated superoxide dismutase (SOD) either alone or in combination on coronary vasomotor dysfunction. 1400W or SOD 24 h alone or their combination improved endothelium-dependent (bradykinin) and -independent (sodium nitroprusside) coronary flow reserve and inhibited enhanced MMP-9 protein and activity. In addition, histopathological study revealed that either 1400W or SOD or their combination reduced superoxide production and nitrotyrosine protein.


CONCLUSIONS
The present study demonstrates for the first time that selective iNOS inhibition or SOD treatment reduces enhanced MMP-9 protein and activity associated with improvement of both, endothelium-dependent and -independent coronary vasomotor function in rat cardiac allografts. This is accompanied by reduction of nitrotyrosine and superoxide production. This suggests that the proteolytic enzyme MMP-9 is an effector molecule of oxidant-mediated coronary vasomotor dysfunction.
Egi
Koso
K
Department of Cardiac Surgery, Ludwig-Maximilians-University, Munich, Germany.
Conrad
Nicole E
NE
Kwan
Jennifer
J
Schulze
Costas
C
Schulz
Richard
R
Wildhirt
Stephen M
SM
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000378:metabolism / Q000503:physiopathology*; D001596:Benzylamines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D016027:Heart Transplantation; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011914:Rats, Inbred BN; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014666:Vasomotor System / Q000187:drug effects / Q000503:physiopathology
D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D013481:Superoxides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D013482:Superoxide Dismutase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9