Abstract
Metabolic syndrome (MS), overlapping type 2 diabetes, hyperlipidemia, and/or hypertension, owing to high-fat diet, poses risk for cardiovascular disease. A critical feature associated with such risk is the functional impairment of endothelial progenitor cells (EPCs). Dipeptidyl dipeptidase-4 inhibitors (DPP-4 i) not only inhibit degradation of incretins to control blood glucose levels, but also improve EPC bioactivity and induce anti-inflammatory effects in tissues. In the present study, we investigated the effects of such an inhibitor, MK-06266, in an ischemia model of MS using diet-induced obese (DIO) mice. EPC bioactivity was examined in MK-0626-administered DIO mice and a non-treated control group, using an EPC colony-forming assay and bone marrow cKit+ Sca-1+ lineage-cells, and peripheral blood-mononuclear cells. Our results showed that, in vitro, the effect of MK-0626 treatment on EPC bioactivities and differentiation was superior compared to the control. Furthermore, microvascular density and pericyte-recruited arteriole number increased in MK-0626-administered mice, but not in the control group. Lineage profiling of isolated cells from ischemic tissues revealed that MK-0626 administration has an inhibitory effect on unproductive inflammation. This occurred via a decrease in the influx of total blood cells and pro-inflammatory cells such as neutrophils, total macrophages, M1, total T-cells, cytotoxic T-cells, and B-cells, with a concomitant increase in number of regeneration-associated cells, such as M2/M ratio and Treg/T-helper. Laser Doppler analysis revealed that at day 14 after ischemic injury, blood perfusion in hindlimb was greater in MK-0626-treated DIO mice, but not in control. In conclusion, the DPP-4 i had a positive effect on EPC differentiation in MS model of DIO mice. Following ischemic injury, DPP-4 i sharply reduced recruitment of pro-inflammatory cells into ischemic tissue and triggered regeneration and reparation, making it a promising therapeutic agent for MS treatment.
Highlights
Vascular regeneration is an initial and essential process for organ regeneration
The frequency of definitive EPCs (dEPCs)-CFUs per peripheral blood (PB) volume sharply decreased in diet-induced obese (DIO) mice compared with that in control mice, while MK-0626-administered mice showed a dramatic improvement in the number of dEPC-CFUs per 1 mL PB (Fig 1B)
These data suggest that Endothelial progenitor cells (EPCs) differentiation in peripheral blood mononuclear cells (PBMNCs) was impaired in DIO mice, and MK-0626 treatment effectively recovered the EPC differentiation ability to similar levels seen in Lean mice
Summary
Endothelial progenitor cells (EPCs) play key roles in vasculogenesis [1] and in regulating angiogenesis [2]. EPC kinetics and bioactivities are essential for vascular regeneration and organogenesis in regenerative medicine. There are several options to stimulate EPC proliferation and biological functions in diabetes that are being actively pursued by researchers [4]. Several cytokines such as stromal cell-derived factor-1 (SDF-1), granulocyte colony stimulating factor (G-CSF), and granulocyte macrophage colony stimulating factor (GM-CSF), angiogenic growth factors such as vascular endothelial growth factor (VEGF), and pharmaceutical drugs such as estrogen and statins augment EPC bioactivities, such as proliferation, differentiation, migration, mobilization, and recruitment of BM-derived EPCs [5, 6]
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