Intracerebroventricular administration of an endothelin ET B-receptor agonist increases expression of matrix metalloproteinase-2 and -9 in rat brain

Matrix metalloproteinases (mmps),a family of zinc-endopeptidases,have a critical role in the pathophysiological responses in damaged brains. mmps are up-regulated in brain pathologies. to clarify the extracellular signals involved in brain mmp production,the effects of endothelins (ets),a family of vasoconstricting peptides,were examined. intracerebroventricular administration of 500 pmol/day ala1,3,11,15-et-1,an etb-receptor agonist,increased the mrnas of mmp2 and mmp9 in rat hippocampus and cerebrum. ala1,3,11,15-et-1 did not affect mrna levels of mmp 1,12,and 14. administration of ala1,3,11,15-et-1 for 7 days also increased the protein content and proteolytic activities of mmp2 and mmp9 in the cerebrum. immunohistochemical observations showed that astrocytes in the hippocampus and the cerebrum of et-infused rats had mmp2 and mmp9 reactivities. in rat cultured astrocytes,both ala1,3,11,15-et-1 (100 nm) and et-1 (100 nm) increased mmp2 and mmp9 mrnas. et-1 stimulated the protein releases and the proteolytic activities of mmp2 and mmp9 from cultured astrocytes. bq788,an etb antagonist,inhibited the effects of et-1 on astrocytic mmp2 and mmp9. the et-induced expression of mmp9,but not mmp2,was inhibited by pyrrolidine dithiocarbamate,proteasome inhibitor i,and mg132. these results suggest that et stimulates astrocytic mmp2 and mmp9 production through et b receptors. ©2010 the japanese pharmacological society.