phenylmercuric-acetate and Brain-Ischemia

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.

Topics: Animals; Apoptosis; Brain Ischemia; Cell Line; Cells, Cultured; Cerebral Cortex; Cysteine; Enzyme Activation; Enzyme Precursors; Humans; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Molecular; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Oxidation-Reduction; Phenylmercuric Acetate; Rats; Recombinant Proteins; Reperfusion; S-Nitrosothiols; Signal Transduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization