Down-regulation of matrix metalloproteinase-9 expression by nitric oxide in lipopolysaccharide-stimulated rat primary astrocytes.
Immunologically activated astrocytes over-express matrix metalloproteinase-9 (MMP-9) and nitric oxide (NO). Because they have both beneficial and detrimental effects on the pathophyiological outcomes of several neurological diseases, their expression should be tightly regulated in the CNS. NO can modify the activity of other proteins either by directly modifying protein structure or regulating the expression of target proteins. In this study, we investigated the role of NO on the expression of MMPs in rat primary astrocytes. Rat primary astrocytes were stimulated with lipopolysaccharide (LPS), resulting in the over-expression of both MMP-9 and NO. Inhibition of NO production using nitric oxide synthase inhibitor, Nomega-nitro-l-arginine methyl ester (l-NAME), further increased MMP-9 expression, suggesting NO inhibits MMP-9 expression. In line with this observation, exogenous addition of NO donor, sodium nitroprusside (SNP) or S-nitroso-N-acetylpenicillamine (SNAP), inhibited MMP-9 expression in astrocytes. The inhibitory effect of NO was mediated by the down-regulation of mRNA and protein levels of MMP-9 but not by the direct modification of the enzymatic activity of MMP-9. The effect of NO on MMP-9 expression was mimicked by dibutyryl-cGMP and inhibited by PKG inhibitor KT5823, suggesting NO regulates MMP-9 expression via guanylate cyclase-PKG pathway. Finally, SNP or dibutyryl-cGMP inhibited the activation of ERK1/2 in LPS-stimulated astrocytes, which is an essential regulator of MMP-9 expression in astrocytes. The regulation of MMP-9 expression by NO may confer additional levels of fine-tuning of the level of MMP-9 during brain inflammatory conditions.
Shin
Chan Young
CY
Department of Pharmacology, School of Medicine, Konkuk University, Republic of Korea.
Lee
Woo Jong
WJ
Choi
Ji Woong
JW
Choi
Min Sik
MS
Ryu
Jae Ryun
JR
Oh
Soon Jin
SJ
Cheong
Jae Hoon
JH
Choi
Eui Yul
EY
Ko
Kwang Ho
KH
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000032:analysis / Q000096:biosynthesis / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9