Dipeptidyl peptidase-4 inhibitor improves neovascularization by increasing circulating endothelial progenitor cells.
OBJECTIVE
Current methods used to treat critical limb ischaemia (CLI) are hampered by a lack of effective strategies, therefore, therapeutic vasculogenesis may open up a new field for the treatment of CLI. In this study we investigated the ability of the DPP-4 inhibitor, sitagliptin, originally used as a hypoglycaemic agent, to induce vasculogenesis in vivo.


METHODS
Sitagliptin were administered daily to C57CL/B6 mice and eGFP transgenic mouse bone marrow-transplanted ICR mice that had undergone hindlimb ischaemic surgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neovasculogenesis and circulating levels of endothelial progenitor cells (EPCs) respectively. Cell surface markers of EPCs and endothelial NOS (eNOS) in vessels were studied.


RESULTS
Sitagliptin elevated plasma glucagon-like peptide-1 (GLP-1) levels in mice subjected to ischaemia, decreased plasma dipeptidyl peptidase-4 (DPP-4) concentration, and augmented ischaemia-induced increases in stromal cell-derived factor-1 (SDF-1) in a dose-dependent manner. Blood flow in the ischaemic limb was significantly improved in mice treated with sitagliptin. Circulating levels of EPCs were also increased after sitagliptin treatment. Sitagliptin also enhanced the expression of CD 34 and eNOS in ischaemic muscle. In addition, sitagliptin promoted EPC mobilization and homing to ischaemic tissue in eGFP transgenic mouse bone marrow-transplanted ICR mice.


CONCLUSIONS
Circulating EPC levels and neovasculogenesis were augmented by the DPP-4 inhibitor, sitagliptin and this effect was dependent on an eNOS-related pathway in a mouse model of hindlimb ischaemia. The results indicate that oral administration of sitagliptin has therapeutic potential as an inducer of vasculogenesis.
Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
Chun-Yao
CY
Huang
Chun-Ming
CM
Shih
Nai-Wen
NW
Tsao
Yi-Wen
YW
Lin
Po-Hsun
PH
Huang
Shinn-Chih
SC
Wu
Ai-Wei
AW
Lee
Yung-Ta
YT
Kao
Nen-Chung
NC
Chang
Hironori
H
Nakagami
Ryuichi
R
Morishita
Keng-Liang
KL
Ou
Wen-Chi
WC
Hou
Cheng-Yen
CY
Lin
Kuo-Gi
KG
Shyu
Feng-Yen
FY
Lin
D000818:Animals; D054377:Chemokine CXCL12 / Q000097:blood; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D000068900:Sitagliptin Phosphate; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*
D054377:Chemokine CXCL12; D054873:Dipeptidyl-Peptidase IV Inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011719:Pyrazines; D014230:Triazoles; D052216:Glucagon-Like Peptide 1; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate