MK-0626, a dipeptidyl peptidase-4 inhibitor, improves neovascularization by increasing both the number of circulating endothelial progenitor cells and endothelial nitric oxide synthetase expression.
Current treatment modalities for critical limb ischemia (CLI) are of limited benefit; therefore, advances in therapeutic vasculogenesis may open an important new avenue for the treatment of CLI. This study examines the therapeutic potential of the DPP-4 inhibitor MK-0626 as a regulator of vasculogenesis in vivo. MK-0626 was administered daily to C57CL/B6 mice and eGFP-labeled bone marrow-transplanted ICR mice that had undergone hind limb ischemia surgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neo-vasculogenesis and the number of circulating endothelial progenitor cells (EPCs), respectively. Cell surface markers of EPCs and the level of endothelial nitric oxide synthase (eNOS) were studied in the vessels. Mice that received MK-0626 had an elevated level of glucagon- like peptide-1 (GLP-1) and a decreased level of dipeptidyl peptidase-4 (DPP-4) in their plasma, in addition to an ischemia-induced increase in the level of stromal cell-derived factor-1 (SDF-1). In C57CL/B6 mice, blood flow in the ischemic limb was significantly improved by treatment with MK-0626. The number of circulating EPCs and both the synthesis and phosphorylation of eNOS were also increased in ischemic thigh muscle after MK-0626 treatment. In contrast, similar effects of MK-0626 were not observed in B6.129P2-Nos3(tm1Unc)/J mice (an eNOS knockout mouse). Additionally, MK-0626 treatment promoted the mobilization and homing of EPCs to ischemic tissue in eGFP transgenic mouse bone marrow-transplanted ICR mice. We conclude that both the number of circulating EPCs and neo-vasculogenesis are increased in response to DPP-4 inhibitor treatment and that this occurs via an eNOS-dependent mechanism. The results highlight the therapeutic vasculogenesis potential of the DPP-4 inhibitor MK-0626 using a hind limb ischemia mouse model.
Chun-Ming
CM
Shih
Yung-Hsiang
YH
Chen
Yi-Wen
YW
Lin
Nai-Wen
NW
Tsao
Shinn-Chih
SC
Wu
Yung-Ta
YT
Kao
Kuang-Hsing
KH
Chiang
Chi-Yuan
CY
Li
Nen-Chung
NC
Chang
Cheng-Yen
CY
Lin
Chun-Yao
CY
Huang
Division of Cardiology, Taipei Medical University Hospital, No. 250, Wu-Hsing Street, Shin-Yi District, Taipei City, Taiwan. g870905@tmu.edu.tw.
Feng-Yen
FY
Lin
D000818:Animals; D016026:Bone Marrow Transplantation; D054377:Chemokine CXCL12 / Q000032:analysis / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000032:analysis / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D066026:Endothelial Progenitor Cells / Q000187:drug effects* / Q000473:pathology; D005121:Extremities / Q000098:blood supply* / Q000473:pathology; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052250:Nitric Oxide Synthase Type III / Q000032:analysis / Q000378:metabolism*; D014230:Triazoles / Q000627:therapeutic use*
D054377:Chemokine CXCL12; D054873:Dipeptidyl-Peptidase IV Inhibitors; C570834:MK0626; D014230:Triazoles; D052250:Nitric Oxide Synthase Type III; D018819:Dipeptidyl Peptidase 4