Abstract 13192: Dipeptidyl Peptidase-4 Inhibitor, Linagliptin, Ameliorates Endothelial Dysfunction and Atherogenesis in Apolipoprotein-e Deficient Mice Through GLP-1 Dependent and Independent Manners
Background: The dipeptidyl peptidase-4 (DDP-4) inhibitors are a novel class of drug for the treatment of diabetes mellitus. Several studies suggested that their anti-inflammatory effects contribute to the prevention of cardiovascular complication of diabetes. This study aimed to investigate whether linagliptin, a xanthine-based DPP-4 inhibitor, attenuates endothelial dysfunction and prevents subsequent atherogenesis in non-diabetic apolipoprotein-E deficient (ApoE KO) mice.
Methods and Results: Linagliptin (10 mg/kg/day) was administered orally to 8-week-old ApoE KO mice for 20 weeks. Linagliptin administration reduced atherosclerotic lesion progression in the aortic arch as determined by en-face Sudan IV staining compared with the control group (P<0.05) without the alteration of metabolic parameters including blood glucose level. Plasma active GLP-1 was significantly higher in the treated group. Histological and quantitative RT-PCR analyses demonstrated that linagliptin decreased macrophages accumulation and the expression of inflammatory molecules (e.g; MCP-1 and VCAM-1) in atherosclerotic aorta (P<0.05, respectively). Furthermore, linagliptin significantly attenuated the impairment of endothelial function in ApoE KO mice, as determined by acetylcholine-dependent vasodilation. These vasoprotective effects of linagliptin were associated with the decreased ROS generation as determined by urinary 8-OHdG level and the expression of NOX-2, in the abdominal aorta. Incubation of aortic segments from C57BL/6 mice with exendin-4 (Ex-4), a GLP-1 analogue, ameliorated palmitic acid (PA)-induced impairment of endothelium-dependent vasodilation. Ex-4 ameliorated impaired phosphorylation of Akt and eNOSSer1177 caused by PA in human umbilical vein endothelial cells (HUVECs). In addition, linagliptin directly attenuated PA-induced and eNOSSer1177 phosphorylation in HUVECs.
Conclusion: Linagliptin inhibited the development of atherogenesis in non-diabetic ApoE KO mice. Our results suggested that linagliptin ameliorated endothelial dysfunction and oxidative stress through GLP-1 dependent and independent manners
Author Disclosures: H.M. Salim: None. D. Fukuda: None. Y. Higashikuni: None. K. Tanaka: None. Y. Hirata: None. S. Yagi: None. T. Soeki: None. M. Shimabukuro: None. M. Sata: None.
- © 2015 by American Heart Association, Inc.