Vildagliptin, a DPP-4 Inhibitor, Attenuates Endothelial Dysfunction and Atherogenesis in Nondiabetic Apolipoprotein E-Deficient Mice

Abstract

Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel antidiabetic agents with possible vascular protection effects. Endothelial dysfunction is an initiation step in atherogenesis. The purpose of this study was to investigate whether vildagliptin (Vilda) attenuates the development of endothelial dysfunction and atherosclerotic lesions in nondiabetic apolipoprotein E-deficient (ApoE −/−) mice. Eight-week-old nondiabetic ApoE −/− mice fed a Westerntype diet received Vilda (50 mg/kg/day) for 20 weeks or 8 weeks. After 20 weeks of treatment, Vilda administration reduced atherogenesis in the aortic arch as determined by en face Sudan IV staining compared with the vehicle group (P < 0.05). Vilda also reduced lipid accumulation (P < 0.05) and vascular cell adhesion molecule-1 (VCAM-1) expression (P < 0.05) and tended to decrease macrophage infiltration (P = 0.05) into atherosclerotic plaques compared with vehicle. After 8 weeks of treatment, endothelium-dependent vascular reactivity was examined. Vilda administration significantly attenuated the impairment of endothelial function in nondiabetic ApoE −/− mice compared with the vehicle group (P < 0.05). Vilda treatment did not alter metabolic parameters, including blood glucose level, in both study protocols. To investigate the mechanism, aortic segments obtained from wild-type mice were incubated with exendin-4 (Ex-4), a glucagon-like peptide-1 (GLP-1) analog, in the presence or absence of lipopolysaccharide (LPS). Ex-4 attenuated the impairment of endothelium-dependent vasodilation induced by LPS (P < 0.01). Furthermore, Ex-4 promoted phosphorylation of eNOS at Ser1177 which was decreased by LPS in human umbilical endothelial cells (P < 0.05). Vilda inhibited the development of endothelial dysfunction and prevented atherogenesis in nondiabetic ApoE −/− mice. Our results suggested that GLP-1-dependent amelioration of endothelial dysfunction is associated with the atheroprotective effects of Vilda.

DPP-4 inhibitor induces FGF21 expression via sirtuin 1 signaling and improves myocardial energy metabolism

“…In a point of view of clinical setting, the dose what we used (50 mg/kg) was high. In previous basic studies using murine model, vilda was administered 5-50 mg/kg by oral gavage [14,15]. We chose higher dose treatment to clarify pleiotropic effect of this drug in addition to antidiabetic effect.…”

“…The DPP-4 inhibitor vildagliptin (vilda) used in this study was provided by Novartis Pharma AG (Basel, Switzerland). For in vivo studies, we used a dose of 50 mg/kg/day of vilda [14,15]. Vilda was given to mice by oral administration using a feeding needle for 4 weeks, beginning at 17 weeks of age.…”

Cytokine Storm Modulation in COVID-19: A Proposed Role for Vitamin D and DPP-4 Inhibitor Combination Therapy (VIDPP-4i)

“…Overall, these findings suggest that vitamin D and DPP-4i administered together exert anti-inflammatory and immunomodulatory actions to a greater extent than vitamin D or DPP-4i administered alone. Moreover, VIDPP-4i may exert protective effects against endothelial dysfunction [97,98], which has been shown to play an important role in COVID-19 pathophysiology [10]. Figure 1 illustrates the potential protective effects of VIDPP-4i against SARS-CoV-2 infection and COVID-19 progression to the hyperinflammatory state and cytokine storm.…”

Role of Glucose-Lowering Medications in Erectile Dysfunction

“…PACAP also has vasorelaxant effects, and, similarly to substance P, improves vascular endothelial growth factor levels [ 165 , 166 ]. Interestingly, vildagliptin, a DPP4i, was recently shown to inhibit the development of endothelial dysfunction and to prevent atherogenesis in non-diabetic apolipoprotein E–deficient mice [ 167 ]. In addition, Ma et al reported that saxagliptin, another DPP4i, suppressed oxidised low-density lipoprotein cholesterol (ox-LDL)-induced endothelial dysfunction in human vascular endothelial cells, by inactivating JNK, AP-1 and NF-κB signalling [ 168 ].…”