The dipeptidyl peptidase-IV inhibitor inhibits the expression of vascular adhesion molecules and inflammatory cytokines in HUVECs via Akt- and AMPK-dependent mechanisms
The dipeptidyl peptidase-IV inhibitor inhibits the expression of vascular adhesion molecules and inflammatory cytokines in HUVECs via Akt- and AMPK-dependent mechanisms
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DOI：
10.1016/j.mce.2015.01.025
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发表时间：
2015-04-15
影响因子：
4.1
通讯作者：
Yoo, Hye Jin
中科院分区：
文献类型：
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作者：
Hwang, Hwan-Jin;Chung, Hye Soo;Yoo, Hye Jin
近年来，二肽基肽酶-IV（DPP-IV）抑制剂作为一种主要的抗高血糖药物，作为动脉粥样硬化等炎症性疾病的可能治疗靶点受到了广泛关注。然而，DPP-IV抑制剂介导血管内皮细胞抗炎作用的直接分子机制尚未阐明。在人脐静脉内皮细胞（HUVEC）和THP-1细胞中分析了DPP-IV抑制剂吉美曲肽的作用。使用蛋白质印迹，我们证明了gemiglitazone有效地增加AMP激活的蛋白激酶（AMPK）和Akt磷酸化的水平以剂量依赖性的方式。脂多糖（LPS）介导的磷酸化核因子-κ B（NF-κ B）和c-Jun N-末端激酶（INK）水平在吉美曲肽治疗后显著降低。此外，吉美曲肽降低LPS诱导的粘附分子和炎性细胞因子的表达，如血管细胞粘附分子-1（VCAM-1）、E-选择素、肿瘤坏死因子-α（TNF-α）、单核细胞趋化蛋白-1（MCP-1）、白细胞介素-1 β（IL-1 β）和IL-6。在巨噬细胞样THP-1细胞中，吉美曲肽有效抑制LPS和低密度脂蛋白（LDL）诱导的泡沫细胞形成。然而，在用AMPK或Akt抑制剂处理后，吉美曲肽在HUVEC和ITIP-1细胞中的这些抗炎和抗动脉粥样硬化作用显著降低。我们的研究结果表明，gemiglavin有效地抑制LPS诱导的促炎作用，在血管内皮细胞通过减弱NF-κ B和JNK信号转导Akt/AMPK依赖的机制。因此，DPP-IV抑制剂吉美曲肽可以直接保护血管内皮免受炎性疾病如动脉粥样硬化的影响。(C)2015爱思唯尔爱尔兰有限公司版权所有。
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-kappa B (NF-kappa B) and c-Jun N-terminal kinase (INK) 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-1 beta (IL-1 beta), 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 antiatherosclerotic effects of gemigliptin in HUVECs and ITIP-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-kappa B 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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.