Modulation of Sirt1/NF-κB interaction of evogliptin is attributed to inhibition of vascular inflammatory response leading to attenuation of atherosclerotic plaque formation.

Abstract

Evogliptin is a novel, potent and selective dipeptidyl peptidase 4 inhibitor that has received approval for use in the treatment of type 2 diabetes in South Korea. In the management of diabetes, it is important to reduce cardiovascular risk factors, as this can decrease the complication and mortality rate. However, the effect of evogliptin on the atherosclerotic progression has not been evaluated. In this study, we examined the effects of evogliptin on the progression of atherosclerosis and its possible mechanism of action. The anti-atherosclerotic effect of evogliptin was evaluated in ApoE-knockout mice fed high-fat diet analysed by plaque lesion formation, lipid profiles and vascular inflammatory response in the atherosclerotic progression. The in vitro effects of evogliptin were verified in endothelial cells analysed by immunoblotting, siRNA gene knockdown, promoter-luciferase assay, immunoprecipitation and adhesion assay. Evogliptin reduced the high-fat diet-induced atherosclerotic plaque area in the ApoE-/- mouse model. Macrophage infiltration into lesions was suppressed in the evogliptin group. In the endothelial cells, evogliptin inhibited inflammatory responses via suppression of adhesion molecules induced by TNF-α. TNF-α-mediated activation of NF-κB was ameliorated by evogliptin via the interaction of NF-κB with SIRT1 (Sirtuin-1). TNF-α-mediated adhesion between endothelial cells and monocytes was inhibited by evogliptin, but this inhibitory effect was reversed by Sirt1 gene knockdown. This study demonstrates that the protective effect of evogliptin on atherosclerotic progression via inhibition of vascular inflammation. The findings imply that evogliptin has potential for anti-atherosclerosis therapy that targets arterial inflammation.

• Authors: Phuc Anh Nguyen, Jong Soon Won, Md Khalilur Rahman, Eun Ju Bae, Min Kyung Cho
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 168 Pg. 452-464 (10 2019) ISSN: 1873-2968 [Electronic] England
• PMID: 31421133 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• 4-(3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl)piperazin-2-one
• NF-kappa B
• Piperazines
• Tumor Necrosis Factor-alpha
• Vascular Cell Adhesion Molecule-1
• Intercellular Adhesion Molecule-1
• Sirt1 protein, mouse
• Sirtuin 1

Topics

• Animals
• Atherosclerosis (chemically induced, drug therapy)
• Cell Line
• Diet, High-Fat (adverse effects)
• Gene Expression Regulation (drug effects)
• Human Umbilical Vein Endothelial Cells
• Humans
• Inflammation (drug therapy)
• Intercellular Adhesion Molecule-1 (genetics, metabolism)
• Mice
• Mice, Knockout, ApoE
• NF-kappa B (genetics, metabolism)
• Piperazines (pharmacology)
• Sirtuin 1 (genetics, metabolism)
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• Vascular Cell Adhesion Molecule-1 (genetics, metabolism)