Publication Date:
2002-08-17
Description:
Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of neurodegenerative diseases and stroke. However, the mechanism of MMP activation remains unclear. We report that MMP activation involves S-nitrosylation. During cerebral ischemia in vivo, MMP-9 colocalized with neuronal nitric oxide synthase. S-Nitrosylation activated MMP-9 in vitro and induced neuronal apoptosis. Mass spectrometry identified the active derivative of MMP-9, both in vitro and in vivo, as a stable sulfinic or sulfonic acid, whose formation was triggered by S-nitrosylation. These findings suggest a potential extracellular proteolysis pathway to neuronal cell death in which S-nitrosylation activates MMPs, and further oxidation results in a stable posttranslational modification with pathological activity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gu, Zezong -- Kaul, Marcus -- Yan, Boxu -- Kridel, Steven J -- Cui, Jiankun -- Strongin, Alex -- Smith, Jeffrey W -- Liddington, Robert C -- Lipton, Stuart A -- AR08505/AR/NIAMS NIH HHS/ -- P01 HD29587/HD/NICHD NIH HHS/ -- R01 AR42750/AR/NIAMS NIH HHS/ -- R01 CA 69306/CA/NCI NIH HHS/ -- R01 EY05477/EY/NEI NIH HHS/ -- R01 EY09024/EY/NEI NIH HHS/ -- R01 NS41207/NS/NINDS NIH HHS/ -- T32 AG00252/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2002 Aug 16;297(5584):1186-90.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Neuroscience and Aging, Program in Cell Adhesion and Extracellular Matrix Biology, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12183632" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
*Apoptosis
;
Brain Ischemia/*enzymology/pathology
;
Cell Line
;
Cells, Cultured
;
Cerebral Cortex/blood supply/*enzymology/pathology
;
Cysteine/*analogs & derivatives/metabolism/pharmacology
;
Enzyme Activation
;
Enzyme Precursors/genetics/metabolism
;
Humans
;
Matrix Metalloproteinase 9/chemistry/*metabolism
;
Mice
;
Mice, Inbred C57BL
;
Mice, Knockout
;
Models, Molecular
;
Neurons/*physiology
;
Nitric Oxide/metabolism
;
Nitric Oxide Synthase/antagonists & inhibitors/metabolism
;
Nitric Oxide Synthase Type I
;
Oxidation-Reduction
;
Phenylmercuric Acetate/*analogs & derivatives/pharmacology
;
Rats
;
Recombinant Proteins/metabolism
;
Reperfusion
;
S-Nitrosothiols/*metabolism/pharmacology
;
Signal Transduction
;
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
