Dipeptidyl peptidase-4 inhibitor improves neovascularization by increasing circulating endothelial progenitor cells

Chun-Yao Huang, Chun-Ming Shih, Nai-Wen Tsao, Yi Wen Lin, Po Hsun Huang, Shinn Chih Wu, Ai-Wei Lee, Yung Ta Kao, Nen-Chung Chang, Hironori Nakagami, Ryuichi Morishita, Keng-Liang Ou, Wen-Chi Hou, Cheng Yen Lin, Kou-Gi Shyu, Feng-Yen Lin

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Background and PurposeCurrent 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. Experimental ApproachSitagliptin 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. Key ResultsSitagliptin 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. CONCLUSION AND IMPLICATIONS 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.

Original languageEnglish
Pages (from-to)1506-1519
Number of pages14
JournalBritish Journal of Pharmacology
Volume167
Issue number7
DOIs
Publication statusPublished - Dec 2012

Keywords

  • dipeptidyl peptidase-IV
  • endothelial progenitor cells

ASJC Scopus subject areas

  • Pharmacology

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