The dipeptidyl peptidase-IV inhibitor inhibits the expression of vascular adhesion molecules and inflammatory cytokines in HUVECs via Akt- and AMPK-dependent mechanisms. (15th April 2015)

• Record Type: Journal Article
• Authors: Hwang, Hwan-Jin; Chung, Hye Soo; Jung, Tae Woo; Ryu, Ja Young; Hong, Ho Cheol; Seo, Ji A.; Kim, Sin Gon; Kim, Nan Hee; Choi, Kyung Mook; Choi, Dong Seop; Baik, Sei Hyun; Yoo, Hye Jin
• Is Part Of: Molecular and cellular endocrinology. Volume 405(2015)
• Page Start: 25
• Page End: 34
• Publication Date: 2015-04-15
• Subjects: Dipeptidyl peptidase-IV inhibitors -- AMP-activated protein kinase -- Inflammation -- Endothelial cells; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2015.01.025
• Languages: English
• ISSNs: 0303-7207

Abstract

Highlights: Gemigliptin effectively attenuated LPS-mediated pro-inflammatory signaling such as NF-κB and JNK in HUVECs and THP-1 cells. Gemigliptin significantly inhibited the expression of vascular adhesion molecules such as VCAM-1 and E-selectin in HUVECs. Gemigliptin efficiently inhibited adhesion of THP-1 cells to HUVECs and foam cell formation in macrophage-like THP-1 cells. These anti-inflammatory and anti-atherosclerotic effects of gemigliptin were mediated by Akt or AMPK phosphorylation. Therefore, gemigliptin may directly protect vascular endothelium against atherosclerosis. Abstract: 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-κB (NF-κB) 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-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-1β (IL-1β), 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-κB 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.