The isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions

被引：78

作者：

Cynis, Holger ^{[1
]}

Hoffmann, Torsten ^{[1
]}

Friedrich, Daniel ^{[1
]}

Kehlen, Astrid ^{[1
]}

Gans, Kathrin ^{[1
]}

Kleinschmidt, Martin ^{[1
]}

Rahfeld, Jens-Ulrich ^{[1
]}

Wolf, Raik ^{[1
]}

Wermann, Michael ^{[1
]}

Stephan, Anett ^{[1
]}

Haegele, Monique ^{[1
]}

Sedlmeier, Reinhard ^{[2
]}

Graubner, Sigrid ^{[2
]}

Jagla, Wolfgang ^{[2
]}

Mueller, Anke ^{[2
]}

Eichentopf, Rico ^{[1
]}

Heiser, Ulrich ^{[1
]}

Seifert, Franziska ^{[3
]}

Quax, Paul H. A. ^{[4
]}

de Vries, Margreet R. ^{[4
]}

Hesse, Isabel ^{[5
]}

Trautwein, Daniela ^{[5
]}

Wollert, Ulrich ^{[5
]}

Berg, Sabine ^{[6
]}

Freyse, Ernst-Joachim ^{[6
]}

Schilling, Stephan ^{[1
]}

Demuth, Hans-Ulrich ^{[1
,2
]}

机构：

[1] Probiodrug AG, Halle, Germany

[2] Ingenium Pharmaceut GmbH, Martinsried, Germany

[3] Univ Gottingen, Albrecht von Haller Inst, Gottingen, Germany

[4] Leiden Univ, Med Ctr, Dept Vasc Surg, Leiden, Netherlands

[5] St Elisabeth & St Barbara Hosp, Dept Vasc Surg, Halle, Germany

[6] Inst Diabet Endocrinol & Metab Dis, Karlsburg, Germany

来源：

EMBO MOLECULAR MEDICINE | 2011年 / 3卷 / 09期

关键词：

CCL2; drug development; glutaminyl cyclases; inflammation; pyroglutamate; CHEMOKINE RECEPTOR ANTAGONISTS; CHANGES NEOINTIMAL HYPERPLASIA; CHEMOATTRACTANT PROTEIN-1; GENE-THERAPY; PYROGLUTAMIC ACID; IN-VIVO; GLYCOSAMINOGLYCAN BINDING; ALZHEIMERS-DISEASE; CC-CHEMOKINE; MCP-1;

D O I：

10.1002/emmm.201100158

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：545 / 558

页数：14

共 53 条

[1] PYROGLUTAMIC ACID - NON-METABOLIC FORMATION, FUNCTION IN PROTEINS AND PEPTIDES, AND CHARACTERISTICS OF THE ENZYMES EFFECTING ITS REMOVAL [J].