Intracerebroventricular administration of an endothelin ETB receptor agonist increases expression of tissue inhibitor of matrix metalloproteinase-1 and -3 in rat brain.
Production of tissue inhibitors of matrix metalloproteinases (TIMPs), a family of secreted proteins with inhibitory actions on matrix metalloproteinases (MMPs), is up-regulated following nerve injuries and is suggested to have protective effects against MMP-mediated tissue damages. To clarify the extracellular signals involved in TIMP production in the brain, the effects of endothelins (ETs), a family of vasoconstricting peptides, were examined. I.c.v. administration of 500 pmol/day Ala(1,3,11,15)-ET-1, an ET(B) receptor agonist, increased the level of TIMP-1 mRNA in rat hippocampus, caudate-putamen and cerebrum. Ala(1,3,11,15)-ET-1 increased the level of TIMP-3 mRNA in the cerebrum, but not in the hippocampus or caudate-putamen. TIMP-2 mRNA was not affected in these brain regions. Ala(1,3,11,15)-ET-1 also stimulated the production of TIMP-1 and TIMP-3 proteins in the cerebrum. Immunohistochemical observations in the hippocampi of Ala(1,3,11,15)-ET-1-infused rats showed that NeuN-positive neurons and glial fibrillary acidic protein-positive astrocytes were immunoreactive for TIMP-1. In the cerebrum, astrocytes had TIMP-1 and TIMP3 reactivity, but neurons did not. In rat cultured astrocytes, both 100 nM Ala(1,3,11,15)-ET-1 and ET-1 increased the mRNA levels and protein release of TIMP-1 and TIMP-3 mRNAs. The effects of ET-1 on astrocytic TIMP-1 and TIMP-3 mRNAs were inhibited by BQ788, an ET(B) antagonist. These findings indicate that activation of brain ET(B) receptors causes production of TIMP-1 and TIMP-3, and suggest the involvement of astrocytes in ET-induced TIMP production.
Koyama
Y
Y
Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University, Tonda-bayashi, Japan. koyamay@osaka-ohtani.ac.jp
Baba
A
A
Matsuda
T
T
D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism*
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D005904:Glial Fibrillary Acidic Protein; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; C061779:endothelin 1, Ala(1,3,11,15)-; D010751:Phosphopyruvate Hydratase