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INFLAMMATION AND IMMUNOPHARMACOLOGY

Nitric Oxide and Cyclic GMP Increase the Expression of Matrix Metalloproteinase-9 in Vascular Smooth Muscle

Departments of Medicine (M.M.-P., A.D.B., I.M.) and Oncology (KG., CC.) University of Alberta, Edmonton, Alberta, Canada; Department of Integrative Biology and Pharmacology, University of Texas Health Sciences Center (M.W.R.), Houston, Texas; and The Cross Cancer Institute (K.G., C.C.); and Pulmonary Research Group (M.M.-P., A.D.B.), Edmonton, Alberta, Canada

Interactions and possible cross talk between inducible nitricoxide synthase (iNOS), cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9), were studied in rat aortic vascular smooth muscle cells stimulated with bacterial lipopolysaccharide (LPS), interferon- (IFN-), and phorbol 12-myristate13-acetate (PMA). The expression and activity of iNOS, COX-2, and MMP-9 were characterized at the transcriptional, protein, and enzyme activity levels. The NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME) was used to investigate the effects of NO on COX-2 and MMP-9 at the transcriptional level. The measurements of mRNAs for these enzymes using real-time polymerase chain reaction (PCR) showed that COX-2 mRNA was up-regulated 2.3-fold, whereas MMP-9 mRNA up-regulation was 11.7-fold in the presence of LPS, IFN-, and PMA. Real-time PCR results indicated that L-NAME exerted an inhibitory effect on COX-2 and MMP-9 mRNA synthesis. Both superoxide dismutase (SOD) and the SOD mimetic Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP) did not modify significantly the up-regulation of these enzymes, indicating that neither superoxide nor peroxynitrite are involved in this mechanism. Furthermore, NO-mediated up-regulation of MMP-9 was cGMP-dependent since 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase, blocked, in a concentration-dependent manner, the increased expression of MMP-9, an effect reversed by 8-bromo-cGMP, a soluble analog of cGMP. Our findings suggest that NO and cGMP are necessary to up-regulate the expression of MMP-9.

Address correspondence to: Dr. A. Dean Befus, Chair in Asthma Research, AstraZeneca Canada Inc., Glaxo-Heritage Asthma Research Laboratories, Department of Medicine, University of Alberta, Edmonton, AB, T6G 2S2, Canada. E-mail: dean.befus{at}ualberta.ca

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