Inhibition of endogenous nitric oxide in the heart enhances matrix metalloproteinase-2 release.
Matrix metalloproteinase (MMP) activity is upregulated in pathologies such as atherosclerosis during which endogenous nitric oxide (NO) biosynthesis is reduced. Diminished levels of NO, an antioxidant species, may result in higher oxidative stress. Oxidants are capable of activating MMPs from their zymogen forms. We examined whether basal biosynthesis of NO in the coronary circulation regulates MMP-2 activity. In isolated rat hearts perfused with Krebs-Henseleit buffer at a constant flow of 10 ml min(-1), we measured the release of MMP-2 into the coronary effluent by gelatin zymography. The main gelatinolytic activity of 72-kDa corresponds to MMP-2. Infusion of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) concentration dependently increased coronary perfusion pressure (CPP) (by 48+/-11 mmHg with 100 microM) and enhanced the release of the 72-kDa MMP-2 in the effluent. Coinfusion of the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP, 1 microM) with L-NAME abolished both the increase in CPP and the enhanced MMP-2 release. The thromboxane A2 mimetic U46619 increased CPP to the same extent as L-NAME without increasing 72-kDa activity in the effluent, suggesting that MMP-2 release is not caused simply by enhanced perfusion pressure. Infusion of either L-NAME or U46619 did not significantly enhance LDH release. L-NAME infusion concentration dependently increased the level of lipid hydroperoxides in homogenates prepared from the perfused hearts. Coinfusion of SNAP prevented this increase. These data reveal another cytoprotective mechanism of endogenous NO biosynthesis in the heart, the inhibition of MMP-2 release.
Wang
Wenjie
W
Cardiovascular Research Group, Department of Pediatrics, 4-62 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Viappiani
Serena
S
Sawicka
Jolanta
J
Schulz
Richard
R
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
D008054:Lipid Peroxides; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D020778:Matrix Metalloproteinase 2; D019331:NG-Nitroarginine Methyl Ester