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

研究成果: 雜誌貢獻文章

53 引文 (Scopus)

摘要

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.
原文英語
頁(從 - 到)1506-1519
頁數14
期刊British Journal of Pharmacology
167
發行號7
DOIs
出版狀態已發佈 - 十二月 2012

指紋

Dipeptidyl-Peptidase IV Inhibitors
Ischemia
Inbred ICR Mouse
Extremities
Hindlimb
Transgenic Mice
Bone Marrow
Dipeptidyl Peptidase 4
Chemokine CXCL12
Glucagon-Like Peptide 1
Therapeutics
Sitagliptin Phosphate
Endothelial Progenitor Cells
Hypoglycemic Agents
Oral Administration
Flow Cytometry
Lasers
Muscles

ASJC Scopus subject areas

  • Pharmacology

引用此文

Dipeptidyl peptidase-4 inhibitor improves neovascularization by increasing circulating endothelial progenitor cells. / Huang, Chun-Yao; Shih, Chun-Ming; Tsao, Nai-Wen; Lin, Yi Wen; Huang, Po Hsun; Wu, Shinn Chih; Lee, Ai-Wei; Kao, Yung Ta; Chang, Nen-Chung; Nakagami, Hironori; Morishita, Ryuichi; Ou, Keng-Liang; Hou, Wen-Chi; Lin, Cheng Yen; Shyu, Kou-Gi; Lin, Feng-Yen.

於: British Journal of Pharmacology, 卷 167, 編號 7, 12.2012, p. 1506-1519.

研究成果: 雜誌貢獻文章

Huang, Chun-Yao ; Shih, Chun-Ming ; Tsao, Nai-Wen ; Lin, Yi Wen ; Huang, Po Hsun ; Wu, Shinn Chih ; Lee, Ai-Wei ; Kao, Yung Ta ; Chang, Nen-Chung ; Nakagami, Hironori ; Morishita, Ryuichi ; Ou, Keng-Liang ; Hou, Wen-Chi ; Lin, Cheng Yen ; Shyu, Kou-Gi ; Lin, Feng-Yen. / Dipeptidyl peptidase-4 inhibitor improves neovascularization by increasing circulating endothelial progenitor cells. 於: British Journal of Pharmacology. 2012 ; 卷 167, 編號 7. 頁 1506-1519.
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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.",
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author = "Chun-Yao Huang and Chun-Ming Shih and Nai-Wen Tsao and Lin, {Yi Wen} and Huang, {Po Hsun} and Wu, {Shinn Chih} and Ai-Wei Lee and Kao, {Yung Ta} and Nen-Chung Chang and Hironori Nakagami and Ryuichi Morishita and Keng-Liang Ou and Wen-Chi Hou and Lin, {Cheng Yen} and Kou-Gi Shyu and Feng-Yen Lin",
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AU - Huang, Chun-Yao

AU - Shih, Chun-Ming

AU - Tsao, Nai-Wen

AU - Lin, Yi Wen

AU - Huang, Po Hsun

AU - Wu, Shinn Chih

AU - Lee, Ai-Wei

AU - Kao, Yung Ta

AU - Chang, Nen-Chung

AU - Nakagami, Hironori

AU - Morishita, Ryuichi

AU - Ou, Keng-Liang

AU - Hou, Wen-Chi

AU - Lin, Cheng Yen

AU - Shyu, Kou-Gi

AU - Lin, Feng-Yen

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N2 - 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.

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