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Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK/eNOS pathway in diabetic mice

BACKGROUND: Endothelial dysfunction has been suggested as a possible causal link between hyperglycemia and microvascular complications in diabetes mellitus. The effect of metformin on endothelial progenitor cells (EPCs) is still unclear. This study was designed to test the hypothesis that metformin...

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Autores principales: Yu, Jia-Wen, Deng, Ya-Ping, Han, Xue, Ren, Guo-Fei, Cai, Jian, Jiang, Guo-Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912824/
https://www.ncbi.nlm.nih.gov/pubmed/27316923
http://dx.doi.org/10.1186/s12933-016-0408-3
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author Yu, Jia-Wen
Deng, Ya-Ping
Han, Xue
Ren, Guo-Fei
Cai, Jian
Jiang, Guo-Jun
author_facet Yu, Jia-Wen
Deng, Ya-Ping
Han, Xue
Ren, Guo-Fei
Cai, Jian
Jiang, Guo-Jun
author_sort Yu, Jia-Wen
collection PubMed
description BACKGROUND: Endothelial dysfunction has been suggested as a possible causal link between hyperglycemia and microvascular complications in diabetes mellitus. The effect of metformin on endothelial progenitor cells (EPCs) is still unclear. This study was designed to test the hypothesis that metformin could accelerate wound healing by improving the impaired EPC functions in streptozotocin-induced diabetic mice. METHODS: Streptozotocin (STZ, 60 mg/kg/d × 5 d, i.p.) was injected to induce type 1 diabetes in male C57BL/6 mice. Mice were treated with metformin (250 mg/kg/d, i.g.) for consecutive 14 days. Wound closure was evaluated by wound area and number of CD31 stained capillaries. Functions of bone marrow-endothelial progenitor cells (BM-EPCs) were assessed by tube formation and migration assays, and expression of AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) was determined by western blot analysis. RESULTS: Metformin accelerated wound closure and stimulated angiogenesis in diabetic mice. The number of circulating EPCs was increased significantly in metformin treated diabetic mice. Abilities of tube formation and migration of BM-EPCs were impaired in diabetic mice, which were improved by metformin. Expression of both phosphorylated-AMPK and phosphorylated-eNOS was significantly increased, and nitric oxide (NO) production was enhanced by metformin in BM-EPCs of diabetic mice. In vitro, metformin improved impaired BM-EPC functions, and increased phosphorylated-eNOS expression and NO production in cultured BM-EPCs caused by high glucose, which was prevented by the AMPK inhibitor compound C. CONCLUSIONS: Our results suggest that metformin could improve BM-EPC functions in STZ-induced diabetic mice, which was possibly dependent on the AMPK/eNOS pathway. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12933-016-0408-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-49128242016-06-19 Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK/eNOS pathway in diabetic mice Yu, Jia-Wen Deng, Ya-Ping Han, Xue Ren, Guo-Fei Cai, Jian Jiang, Guo-Jun Cardiovasc Diabetol Original Investigation BACKGROUND: Endothelial dysfunction has been suggested as a possible causal link between hyperglycemia and microvascular complications in diabetes mellitus. The effect of metformin on endothelial progenitor cells (EPCs) is still unclear. This study was designed to test the hypothesis that metformin could accelerate wound healing by improving the impaired EPC functions in streptozotocin-induced diabetic mice. METHODS: Streptozotocin (STZ, 60 mg/kg/d × 5 d, i.p.) was injected to induce type 1 diabetes in male C57BL/6 mice. Mice were treated with metformin (250 mg/kg/d, i.g.) for consecutive 14 days. Wound closure was evaluated by wound area and number of CD31 stained capillaries. Functions of bone marrow-endothelial progenitor cells (BM-EPCs) were assessed by tube formation and migration assays, and expression of AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) was determined by western blot analysis. RESULTS: Metformin accelerated wound closure and stimulated angiogenesis in diabetic mice. The number of circulating EPCs was increased significantly in metformin treated diabetic mice. Abilities of tube formation and migration of BM-EPCs were impaired in diabetic mice, which were improved by metformin. Expression of both phosphorylated-AMPK and phosphorylated-eNOS was significantly increased, and nitric oxide (NO) production was enhanced by metformin in BM-EPCs of diabetic mice. In vitro, metformin improved impaired BM-EPC functions, and increased phosphorylated-eNOS expression and NO production in cultured BM-EPCs caused by high glucose, which was prevented by the AMPK inhibitor compound C. CONCLUSIONS: Our results suggest that metformin could improve BM-EPC functions in STZ-induced diabetic mice, which was possibly dependent on the AMPK/eNOS pathway. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12933-016-0408-3) contains supplementary material, which is available to authorized users. BioMed Central 2016-06-18 /pmc/articles/PMC4912824/ /pubmed/27316923 http://dx.doi.org/10.1186/s12933-016-0408-3 Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Original Investigation
Yu, Jia-Wen
Deng, Ya-Ping
Han, Xue
Ren, Guo-Fei
Cai, Jian
Jiang, Guo-Jun
Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK/eNOS pathway in diabetic mice
title Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK/eNOS pathway in diabetic mice
title_full Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK/eNOS pathway in diabetic mice
title_fullStr Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK/eNOS pathway in diabetic mice
title_full_unstemmed Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK/eNOS pathway in diabetic mice
title_short Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK/eNOS pathway in diabetic mice
title_sort metformin improves the angiogenic functions of endothelial progenitor cells via activating ampk/enos pathway in diabetic mice
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912824/
https://www.ncbi.nlm.nih.gov/pubmed/27316923
http://dx.doi.org/10.1186/s12933-016-0408-3
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