Dipeptidyl peptidase-4 inhibition with linagliptin prevents western diet-induced vascular abnormalities in female mice

Cardiovascular Diabetology

Original Investigation

Thomas Klein¹  Melvin R. Hayden²  James R. Sowers³  Vincent G. DeMarco³  Guanghong Jia⁴  Camila Manrique⁴  Mona Garro⁴  Annayya R. Aroor⁴  Javad Habibi⁴  Gerald A. Meininger⁵  Luis A. Martinez-Lemus⁵  Francisco I. Ramirez-Perez⁵ 

[1] Boehringer Ingelheim Pharma, Ingelheim Am Rhein, Germany;Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Missouri-Columbia School of Medicine, One Hospital Drive, 65212, Columbia, MO, USA;MU Diabetes and Cardiovascular Research Center, University of Missouri, School of Medicine, Columbia, USA;Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Missouri-Columbia School of Medicine, One Hospital Drive, 65212, Columbia, MO, USA;MU Diabetes and Cardiovascular Research Center, University of Missouri, School of Medicine, Columbia, USA;Department of Medical Pharmacology and Physiology, University of Missouri, School of Medicine, Columbia, USA;Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, USA;The Dalton Cardiovascular Research Center, Columbia, USA;Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Missouri-Columbia School of Medicine, One Hospital Drive, 65212, Columbia, MO, USA;MU Diabetes and Cardiovascular Research Center, University of Missouri, School of Medicine, Columbia, USA;Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, USA;Department of Medical Pharmacology and Physiology, University of Missouri, School of Medicine, Columbia, USA;The Dalton Cardiovascular Research Center, Columbia, USA;

关键词: Pulse wave velocity;    Atomic force microscopy;   

DOI  :  10.1186/s12933-016-0414-5

 received in 2016-04-05, accepted in 2016-06-23,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundVascular stiffening, a risk factor for cardiovascular disease, is accelerated, particularly in women with obesity and type 2 diabetes. Preclinical evidence suggests that dipeptidylpeptidase-4 (DPP-4) inhibitors may have cardiovascular benefits independent of glycemic lowering effects. Recent studies show that consumption of a western diet (WD) high in fat and simple sugars induces aortic stiffening in female C57BL/6J mice in advance of increasing blood pressure. The aims of this study were to determine whether administration of the DPP-4 inhibitor, linagliptin (LGT), prevents the development of aortic and endothelial stiffness induced by a WD in female mice.MethodsC56Bl6/J female mice were fed a WD for 4 months. Aortic stiffness and ex vivo endothelial stiffness were evaluated by Doppler pulse wave velocity (PWV) and atomic force microscopy (AFM), respectively. In addition, we examined aortic vasomotor responses and remodeling markers via immunohistochemistry. Results were analyzed via 2-way ANOVA, p < 0.05 was considered as statistically significant.ResultsCompared to mice fed a control diet (CD), WD-fed mice exhibited a 24 % increase in aortic PWV, a five-fold increase in aortic endothelial stiffness, and impaired endothelium-dependent vasodilation. In aorta, these findings were accompanied by medial wall thickening, adventitial fibrosis, increased fibroblast growth factor 23 (FGF-23), decreased Klotho, enhanced oxidative stress, and endothelial cell ultrastructural changes, all of which were prevented with administration of LGT.ConclusionsThe present findings support the notion that DPP-4 plays a role in development of WD-induced aortic stiffening, vascular oxidative stress, endothelial dysfunction, and vascular remodeling. Whether, DPP-4 inhibition could be a therapeutic tool used to prevent the development of aortic stiffening and the associated cardiovascular complications in obese and diabetic females remains to be elucidated.

【 授权许可】

CC BY   
© The Author(s) 2016