PMID- 28630262 OWN - NLM STAT- MEDLINE DCOM- 20180403 LR - 20181113 IS - 2047-9980 (Electronic) IS - 2047-9980 (Linking) VI - 6 IP - 6 DP - 2017 Jun 19 TI - Dipeptidyl Peptidase-4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation. LID - 10.1161/JAHA.116.004777 [doi] LID - e004777 AB - BACKGROUND: Chronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP-4 (dipeptidyl peptidase-4) inhibitors have anti-inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP-4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model. METHODS AND RESULTS: IAs were surgically induced in 7-week-old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide-treated RAW264.7 macrophages. In the anagliptin-treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP-1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide-stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor alpha, MCP-1, and IL-6 (interleukin 6) independent of GLP-1 (glucagon-like peptide 1), the key mediator in the antidiabetic effects of DPP-4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal-regulated kinase 5), which mediates the anti-inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP-1 and IL-6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro. CONCLUSIONS: A DPP-4 inhibitor, anagliptin, prevents the growth of IAs via its anti-inflammatory effects on macrophages. CI - (c) 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. FAU - Ikedo, Taichi AU - Ikedo T AD - Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. AD - Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. FAU - Minami, Manabu AU - Minami M AD - Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan mminami@kuhp.kyoto-u.ac.jp hkataoka@ncvc.go.jp. FAU - Kataoka, Hiroharu AU - Kataoka H AD - Department of Neurosurgery, National Cerebral and Cardiovascular Center, Suita Osaka, Japan mminami@kuhp.kyoto-u.ac.jp hkataoka@ncvc.go.jp. FAU - Hayashi, Kosuke AU - Hayashi K AD - Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. AD - Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. FAU - Nagata, Manabu AU - Nagata M AD - Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. AD - Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. FAU - Fujikawa, Risako AU - Fujikawa R AD - Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. FAU - Higuchi, Sei AU - Higuchi S AD - Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. FAU - Yasui, Mika AU - Yasui M AD - Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. FAU - Aoki, Tomohiro AU - Aoki T AD - Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan. AD - Core Research for Evolutional Science and Technology, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan. FAU - Fukuda, Miyuki AU - Fukuda M AD - Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. AD - Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan. FAU - Yokode, Masayuki AU - Yokode M AD - Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. FAU - Miyamoto, Susumu AU - Miyamoto S AD - Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. LA - eng PT - Journal Article DEP - 20170619 PL - England TA - J Am Heart Assoc JT - Journal of the American Heart Association JID - 101580524 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Cytokines) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Inflammation Mediators) RN - 0 (Pyrimidines) RN - 0 (Rela protein, mouse) RN - 0 (Transcription Factor RelA) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 7) RN - EC 3.4.14.5 (DPP4 protein, rat) RN - EC 3.4.14.5 (Dipeptidyl Peptidase 4) RN - K726J96838 (anagliptin) SB - IM MH - Animals MH - Anti-Inflammatory Agents/*pharmacology MH - Brain/*drug effects/enzymology/immunology MH - Cell Movement/*drug effects MH - Cytokines/metabolism MH - Dipeptidyl Peptidase 4/*metabolism MH - Dipeptidyl-Peptidase IV Inhibitors/*pharmacology MH - Disease Models, Animal MH - Enzyme Activation MH - Inflammation Mediators/metabolism MH - Intracranial Aneurysm/enzymology/immunology/pathology/*prevention & control MH - Macrophage Activation/*drug effects MH - Macrophages/*drug effects/enzymology/immunology MH - Male MH - Mice MH - Mitogen-Activated Protein Kinase 7/metabolism MH - Phosphorylation MH - Pyrimidines/*pharmacology MH - RAW 264.7 Cells MH - Rats, Sprague-Dawley MH - Signal Transduction/drug effects MH - Transcription Factor RelA/metabolism PMC - PMC5669147 OTO - NOTNLM OT - dipeptidyl peptidase-4 inhibitor OT - extracellular signal-regulated kinase 5 OT - glucagon-like peptide-1 OT - intracranial aneurysm OT - macrophage EDAT- 2017/06/21 06:00 MHDA- 2018/04/04 06:00 PMCR- 2017/06/01 CRDT- 2017/06/21 06:00 PHST- 2017/06/21 06:00 [entrez] PHST- 2017/06/21 06:00 [pubmed] PHST- 2018/04/04 06:00 [medline] PHST- 2017/06/01 00:00 [pmc-release] AID - JAHA.116.004777 [pii] AID - JAH32322 [pii] AID - 10.1161/JAHA.116.004777 [doi] PST - epublish SO - J Am Heart Assoc. 2017 Jun 19;6(6):e004777. doi: 10.1161/JAHA.116.004777.