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A novel imidazolinone metformin‐methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF‐1α pathway
Peripheral arterial disease (PAD) is one of the major complications of diabetes due to an impairment in angiogenesis. Since there is currently no drug with satisfactory efficacy to enhance blood vessel formation, discovering therapies to improve angiogenesis is critical. An imidazolinone metabolite...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237315/ https://www.ncbi.nlm.nih.gov/pubmed/34105824 http://dx.doi.org/10.1096/fj.202002674RR |
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author | Nguyen, Huong Koh, Jia Yi Li, Hainan Islas‐Robles, Argel Meda Venkata, Sai Pranathi Wang, Jie‐Mei Monks, Terrence J. |
author_facet | Nguyen, Huong Koh, Jia Yi Li, Hainan Islas‐Robles, Argel Meda Venkata, Sai Pranathi Wang, Jie‐Mei Monks, Terrence J. |
author_sort | Nguyen, Huong |
collection | PubMed |
description | Peripheral arterial disease (PAD) is one of the major complications of diabetes due to an impairment in angiogenesis. Since there is currently no drug with satisfactory efficacy to enhance blood vessel formation, discovering therapies to improve angiogenesis is critical. An imidazolinone metabolite of the metformin‐methylglyoxal scavenging reaction, (E)‐1,1‐dimethyl‐2‐(5‐methyl‐4‐oxo‐4,5‐dihydro‐1H‐imidazol‐2‐yl) guanidine (IMZ), was recently characterized and identified in the urine of type‐2 diabetic patients. Here, we report the pro‐angiogenesis effect of IMZ (increased aortic sprouting, cell migration, network formation, and upregulated multiple pro‐angiogenic factors) in human umbilical vein endothelial cells. Using genetic and pharmacological approaches, we showed that IMZ augmented angiogenesis by activating the endothelial nitric oxide synthase (eNOS)/hypoxia‐inducible factor‐1 alpha (HIF‐1α) pathway. Furthermore, IMZ significantly promoted capillary density in the in vivo Matrigel plug angiogenesis model. Finally, the role of IMZ in post‐ischemic angiogenesis was examined in a chronic hyperglycemia mouse model subjected to hind limb ischemia. We observed improved blood perfusion, increased capillary density, and reduced tissue necrosis in mice receiving IMZ compared to control mice. Our data demonstrate the pro‐angiogenic effects of IMZ, its underlying mechanism, and provides a structural basis for the development of potential pro‐angiogenic agents for the treatment of PAD. |
format | Online Article Text |
id | pubmed-8237315 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82373152021-07-01 A novel imidazolinone metformin‐methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF‐1α pathway Nguyen, Huong Koh, Jia Yi Li, Hainan Islas‐Robles, Argel Meda Venkata, Sai Pranathi Wang, Jie‐Mei Monks, Terrence J. FASEB J Research Articles Peripheral arterial disease (PAD) is one of the major complications of diabetes due to an impairment in angiogenesis. Since there is currently no drug with satisfactory efficacy to enhance blood vessel formation, discovering therapies to improve angiogenesis is critical. An imidazolinone metabolite of the metformin‐methylglyoxal scavenging reaction, (E)‐1,1‐dimethyl‐2‐(5‐methyl‐4‐oxo‐4,5‐dihydro‐1H‐imidazol‐2‐yl) guanidine (IMZ), was recently characterized and identified in the urine of type‐2 diabetic patients. Here, we report the pro‐angiogenesis effect of IMZ (increased aortic sprouting, cell migration, network formation, and upregulated multiple pro‐angiogenic factors) in human umbilical vein endothelial cells. Using genetic and pharmacological approaches, we showed that IMZ augmented angiogenesis by activating the endothelial nitric oxide synthase (eNOS)/hypoxia‐inducible factor‐1 alpha (HIF‐1α) pathway. Furthermore, IMZ significantly promoted capillary density in the in vivo Matrigel plug angiogenesis model. Finally, the role of IMZ in post‐ischemic angiogenesis was examined in a chronic hyperglycemia mouse model subjected to hind limb ischemia. We observed improved blood perfusion, increased capillary density, and reduced tissue necrosis in mice receiving IMZ compared to control mice. Our data demonstrate the pro‐angiogenic effects of IMZ, its underlying mechanism, and provides a structural basis for the development of potential pro‐angiogenic agents for the treatment of PAD. John Wiley and Sons Inc. 2021-06-09 2021-07 /pmc/articles/PMC8237315/ /pubmed/34105824 http://dx.doi.org/10.1096/fj.202002674RR Text en © 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles Nguyen, Huong Koh, Jia Yi Li, Hainan Islas‐Robles, Argel Meda Venkata, Sai Pranathi Wang, Jie‐Mei Monks, Terrence J. A novel imidazolinone metformin‐methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF‐1α pathway |
title | A novel imidazolinone metformin‐methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF‐1α pathway |
title_full | A novel imidazolinone metformin‐methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF‐1α pathway |
title_fullStr | A novel imidazolinone metformin‐methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF‐1α pathway |
title_full_unstemmed | A novel imidazolinone metformin‐methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF‐1α pathway |
title_short | A novel imidazolinone metformin‐methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF‐1α pathway |
title_sort | novel imidazolinone metformin‐methylglyoxal metabolite promotes endothelial cell angiogenesis via the enos/hif‐1α pathway |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237315/ https://www.ncbi.nlm.nih.gov/pubmed/34105824 http://dx.doi.org/10.1096/fj.202002674RR |
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