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EMBO Mol Med ; 3(9): 545-58, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21774078

RESUMO

Acute and chronic inflammatory disorders are characterized by detrimental cytokine and chemokine expression. Frequently, the chemotactic activity of cytokines depends on a modified N-terminus of the polypeptide. Among those, the N-terminus of monocyte chemoattractant protein 1 (CCL2 and MCP-1) is modified to a pyroglutamate (pE-) residue protecting against degradation in vivo. Here, we show that the N-terminal pE-formation depends on glutaminyl cyclase activity. The pE-residue increases stability against N-terminal degradation by aminopeptidases and improves receptor activation and signal transduction in vitro. Genetic ablation of the glutaminyl cyclase iso-enzymes QC (QPCT) or isoQC (QPCTL) revealed a major role of isoQC for pE(1) -CCL2 formation and monocyte infiltration. Consistently, administration of QC-inhibitors in inflammatory models, such as thioglycollate-induced peritonitis reduced monocyte infiltration. The pharmacologic efficacy of QC/isoQC-inhibition was assessed in accelerated atherosclerosis in ApoE3*Leiden mice, showing attenuated atherosclerotic pathology following chronic oral treatment. Current strategies targeting CCL2 are mainly based on antibodies or spiegelmers. The application of small, orally available inhibitors of glutaminyl cyclases represents an alternative therapeutic strategy to treat CCL2-driven disorders such as atherosclerosis/restenosis and fibrosis.


Assuntos
Aminoaciltransferases/metabolismo , Movimento Celular , Quimiocina CCL2/metabolismo , Inflamação/imunologia , Inflamação/patologia , Isoenzimas/metabolismo , Monócitos/metabolismo , Animais , Aterosclerose/imunologia , Aterosclerose/patologia , Linhagem Celular , Quimiocina CCL2/antagonistas & inibidores , Feminino , Inativação Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/enzimologia
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