PMID- 25661535 OWN - NLM STAT- MEDLINE DCOM- 20151221 LR - 20150317 IS - 1872-8057 (Electronic) IS - 0303-7207 (Linking) VI - 405 DP - 2015 Apr 15 TI - The dipeptidyl peptidase-IV inhibitor inhibits the expression of vascular adhesion molecules and inflammatory cytokines in HUVECs via Akt- and AMPK-dependent mechanisms. PG - 25-34 LID - S0303-7207(15)00036-2 [pii] LID - 10.1016/j.mce.2015.01.025 [doi] AB - Recently, dipeptidyl peptidase-IV (DPP-IV) inhibitor, a major anti-hyperglycemic agent, has received substantial attention as a possible therapeutic target for inflammatory diseases such as atherosclerosis. However, the direct molecular mechanisms through which DPP-IV inhibitor mediates anti-inflammatory effects in vascular endothelial cells have not been clarified. The effects of the DPP-IV inhibitor, gemigliptin, were analyzed in human umbilical vein endothelial cells (HUVECs) and THP-1 cells. Using Western blotting, we demonstrated that gemigliptin efficiently increased the level of AMP-activated protein kinase (AMPK) and Akt phosphorylation in a dose-dependent manner. The levels of lipopolysaccharide (LPS)-mediated phosphorylated nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK) were significantly decreased after gemigliptin treatment. Furthermore, gemigliptin reduced LPS-induced expression of adhesion molecules and inflammatory cytokines such as vascular cell adhesion molecule-1 (VCAM-1), E-selectin, tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), interleukin-1beta (IL-1beta), and IL-6 in HUVECs. In macrophage-like THP-1 cells, gemigliptin effectively inhibited LPS- and low-density lipoprotein (LDL)-induced foam cell formation. However, these anti-inflammatory and anti-atherosclerotic effects of gemigliptin in HUVECs and THP-1 cells were significantly reduced after treatment with an AMPK or an Akt inhibitor. Our results suggest that gemigliptin efficiently inhibited LPS-induced pro-inflammatory effects in vascular endothelial cells by attenuating NF-kappaB and JNK signaling via Akt/AMPK-dependent mechanisms. Therefore, the DPP-IV inhibitor, gemigliptin, may directly protect the vascular endothelium against inflammatory diseases such as atherosclerosis. CI - Copyright (c) 2015 Elsevier Ireland Ltd. All rights reserved. FAU - Hwang, Hwan-Jin AU - Hwang HJ AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea. FAU - Chung, Hye Soo AU - Chung HS AD - Division of Endocrinology, Department of Medicine, Myongji Hospital, Goyang, Korea. FAU - Jung, Tae Woo AU - Jung TW AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea. FAU - Ryu, Ja Young AU - Ryu JY AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea. FAU - Hong, Ho Cheol AU - Hong HC AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea. FAU - Seo, Ji A AU - Seo JA AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea. FAU - Kim, Sin Gon AU - Kim SG AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea. FAU - Kim, Nan Hee AU - Kim NH AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea. FAU - Choi, Kyung Mook AU - Choi KM AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea. FAU - Choi, Dong Seop AU - Choi DS AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea. FAU - Baik, Sei Hyun AU - Baik SH AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea. FAU - Yoo, Hye Jin AU - Yoo HJ AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea. Electronic address: deisy21@naver.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150204 PL - Ireland TA - Mol Cell Endocrinol JT - Molecular and cellular endocrinology JID - 7500844 RN - 0 (Cytokines) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (E-Selectin) RN - 0 (ICAM1 protein, human) RN - 0 (LC15-0444) RN - 0 (Lipopolysaccharides) RN - 0 (Piperidones) RN - 0 (Pyrimidines) RN - 0 (Vascular Cell Adhesion Molecule-1) RN - 126547-89-5 (Intercellular Adhesion Molecule-1) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.4.3 (Adenylate Kinase) SB - IM MH - Adenylate Kinase/metabolism MH - Cell Adhesion MH - Cells, Cultured MH - Cytokines/genetics/*metabolism MH - Dipeptidyl-Peptidase IV Inhibitors/*pharmacology MH - E-Selectin/metabolism MH - Gene Expression/*drug effects MH - Human Umbilical Vein Endothelial Cells/drug effects/immunology/*metabolism MH - Humans MH - Intercellular Adhesion Molecule-1/metabolism MH - Lipopolysaccharides/pharmacology MH - Macrophages/drug effects/immunology MH - Piperidones/*pharmacology MH - Proto-Oncogene Proteins c-akt/metabolism MH - Pyrimidines/*pharmacology MH - Signal Transduction MH - Vascular Cell Adhesion Molecule-1/metabolism OTO - NOTNLM OT - AMP-activated protein kinase OT - Dipeptidyl peptidase-IV inhibitors OT - Endothelial cells OT - Inflammation EDAT- 2015/02/11 06:00 MHDA- 2015/12/22 06:00 CRDT- 2015/02/10 06:00 PHST- 2014/08/19 00:00 [received] PHST- 2015/01/14 00:00 [revised] PHST- 2015/01/16 00:00 [accepted] PHST- 2015/02/10 06:00 [entrez] PHST- 2015/02/11 06:00 [pubmed] PHST- 2015/12/22 06:00 [medline] AID - S0303-7207(15)00036-2 [pii] AID - 10.1016/j.mce.2015.01.025 [doi] PST - ppublish SO - Mol Cell Endocrinol. 2015 Apr 15;405:25-34. doi: 10.1016/j.mce.2015.01.025. Epub 2015 Feb 4.