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Arginine:Glycine Amidinotransferase Is Essential for Creatine Supply in Mice During Chronic Hypoxia
Objective: Chronic hypoxia induces pulmonary and cardiovascular pathologies, including pulmonary hypertension (PH). L-arginine:glycine amidinotransferase (AGAT) is essential for homoarginine (hArg) and guanidinoacetate synthesis, the latter being converted to creatine by guanidinoacetate methyltrans...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416470/ https://www.ncbi.nlm.nih.gov/pubmed/34483959 http://dx.doi.org/10.3389/fphys.2021.703069 |
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author | Hannemann, Juliane Cordts, Kathrin Seniuk, Anika Choe, Chi-un Schmidt-Hutten, Lena Duque Escobar, Jorge Weinberger, Florian Böger, Rainer Schwedhelm, Edzard |
author_facet | Hannemann, Juliane Cordts, Kathrin Seniuk, Anika Choe, Chi-un Schmidt-Hutten, Lena Duque Escobar, Jorge Weinberger, Florian Böger, Rainer Schwedhelm, Edzard |
author_sort | Hannemann, Juliane |
collection | PubMed |
description | Objective: Chronic hypoxia induces pulmonary and cardiovascular pathologies, including pulmonary hypertension (PH). L-arginine:glycine amidinotransferase (AGAT) is essential for homoarginine (hArg) and guanidinoacetate synthesis, the latter being converted to creatine by guanidinoacetate methyltransferase. Low hArg concentrations are associated with cardiovascular morbidity and predict mortality in patients with PH. We therefore aimed to investigate the survival and cardiac outcome of AGAT knockout (Agat(−/−)) mice under hypoxia and a possible rescue of the phenotype. Methods:Agat(−/−) mice and wild-type (WT) littermates were subjected to normoxia or normobaric hypoxia (10% oxygen) for 4 weeks. A subgroup of Agat(−/−) mice was supplemented with 1% creatine from weaning. Survival, hematocrit, blood lactate and glucose, heart weight-to-tibia length (HW/TL) ratio, hArg plasma concentration, and Agat and Gamt expression in lung, liver, and kidneys were evaluated. Results: After 6 h of hypoxia, blood lactate was lower in Agat(−/−)-mice as compared to normoxia (p < 0.001). Agat(−/−) mice died within 2 days of hypoxia, whereas Agat(−/−) mice supplemented with creatine and WT mice survived until the end of the study. In WT mice, hematocrit (74 ± 4 vs. 55 ± 2%, mean ± SD, p < 0.001) and HW/TL (9.9 ± 1.3 vs. 7.3 ± 0.7 mg/mm, p < 0.01) were higher in hypoxia, while hArg plasma concentration (0.25 ± 0.06 vs. 0.38 ± 0.12 μmol/L, p < 0.01) was lower. Agat and Gamt expressions were differentially downregulated by hypoxia in lung, liver, and kidneys. Conclusion:Agat and Gamt are downregulated in hypoxia. Agat(−/−) mice are nonviable in hypoxia. Creatine rescues the lethal phenotype, but it does not reduce right ventricular hypertrophy of Agat(−/−) mice in hypoxia. |
format | Online Article Text |
id | pubmed-8416470 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-84164702021-09-04 Arginine:Glycine Amidinotransferase Is Essential for Creatine Supply in Mice During Chronic Hypoxia Hannemann, Juliane Cordts, Kathrin Seniuk, Anika Choe, Chi-un Schmidt-Hutten, Lena Duque Escobar, Jorge Weinberger, Florian Böger, Rainer Schwedhelm, Edzard Front Physiol Physiology Objective: Chronic hypoxia induces pulmonary and cardiovascular pathologies, including pulmonary hypertension (PH). L-arginine:glycine amidinotransferase (AGAT) is essential for homoarginine (hArg) and guanidinoacetate synthesis, the latter being converted to creatine by guanidinoacetate methyltransferase. Low hArg concentrations are associated with cardiovascular morbidity and predict mortality in patients with PH. We therefore aimed to investigate the survival and cardiac outcome of AGAT knockout (Agat(−/−)) mice under hypoxia and a possible rescue of the phenotype. Methods:Agat(−/−) mice and wild-type (WT) littermates were subjected to normoxia or normobaric hypoxia (10% oxygen) for 4 weeks. A subgroup of Agat(−/−) mice was supplemented with 1% creatine from weaning. Survival, hematocrit, blood lactate and glucose, heart weight-to-tibia length (HW/TL) ratio, hArg plasma concentration, and Agat and Gamt expression in lung, liver, and kidneys were evaluated. Results: After 6 h of hypoxia, blood lactate was lower in Agat(−/−)-mice as compared to normoxia (p < 0.001). Agat(−/−) mice died within 2 days of hypoxia, whereas Agat(−/−) mice supplemented with creatine and WT mice survived until the end of the study. In WT mice, hematocrit (74 ± 4 vs. 55 ± 2%, mean ± SD, p < 0.001) and HW/TL (9.9 ± 1.3 vs. 7.3 ± 0.7 mg/mm, p < 0.01) were higher in hypoxia, while hArg plasma concentration (0.25 ± 0.06 vs. 0.38 ± 0.12 μmol/L, p < 0.01) was lower. Agat and Gamt expressions were differentially downregulated by hypoxia in lung, liver, and kidneys. Conclusion:Agat and Gamt are downregulated in hypoxia. Agat(−/−) mice are nonviable in hypoxia. Creatine rescues the lethal phenotype, but it does not reduce right ventricular hypertrophy of Agat(−/−) mice in hypoxia. Frontiers Media S.A. 2021-08-18 /pmc/articles/PMC8416470/ /pubmed/34483959 http://dx.doi.org/10.3389/fphys.2021.703069 Text en Copyright © 2021 Hannemann, Cordts, Seniuk, Choe, Schmidt-Hutten, Duque Escobar, Weinberger, Böger and Schwedhelm. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Physiology Hannemann, Juliane Cordts, Kathrin Seniuk, Anika Choe, Chi-un Schmidt-Hutten, Lena Duque Escobar, Jorge Weinberger, Florian Böger, Rainer Schwedhelm, Edzard Arginine:Glycine Amidinotransferase Is Essential for Creatine Supply in Mice During Chronic Hypoxia |
title | Arginine:Glycine Amidinotransferase Is Essential for Creatine Supply in Mice During Chronic Hypoxia |
title_full | Arginine:Glycine Amidinotransferase Is Essential for Creatine Supply in Mice During Chronic Hypoxia |
title_fullStr | Arginine:Glycine Amidinotransferase Is Essential for Creatine Supply in Mice During Chronic Hypoxia |
title_full_unstemmed | Arginine:Glycine Amidinotransferase Is Essential for Creatine Supply in Mice During Chronic Hypoxia |
title_short | Arginine:Glycine Amidinotransferase Is Essential for Creatine Supply in Mice During Chronic Hypoxia |
title_sort | arginine:glycine amidinotransferase is essential for creatine supply in mice during chronic hypoxia |
topic | Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416470/ https://www.ncbi.nlm.nih.gov/pubmed/34483959 http://dx.doi.org/10.3389/fphys.2021.703069 |
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