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In Vivo Activation of AMP-Activated Protein Kinase Attenuates Diabetes-Enhanced Degradation of GTP Cyclohydrolase I
OBJECTIVE: The activation of AMP-activated protein kinase (AMPK) has been reported to improve endothelial function. However, the targets of AMPK in endothelial cells remain poorly defined. The aim of this study was to test whether AMPK suppresses the degradation of GTP-cyclohydrolase (GTPCH I), a ke...
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Formato: | Texto |
Lenguaje: | English |
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American Diabetes Association
2009
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712774/ https://www.ncbi.nlm.nih.gov/pubmed/19528375 http://dx.doi.org/10.2337/db09-0267 |
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author | Wang, Shuangxi Xu, Jian Song, Ping Viollet, Benoit Zou, Ming-Hui |
author_facet | Wang, Shuangxi Xu, Jian Song, Ping Viollet, Benoit Zou, Ming-Hui |
author_sort | Wang, Shuangxi |
collection | PubMed |
description | OBJECTIVE: The activation of AMP-activated protein kinase (AMPK) has been reported to improve endothelial function. However, the targets of AMPK in endothelial cells remain poorly defined. The aim of this study was to test whether AMPK suppresses the degradation of GTP-cyclohydrolase (GTPCH I), a key event in vascular endothelial dysfunction in diabetes. RESEARCH DESIGN AND METHODS: Both human umbilical vein endothelial cells and aortas isolated from streptozotocin-injected diabetic mice were assayed for phospho-AMPK (Thr172), GTPCH I, tetrahydrobiopterin (BH4), and endothelial functions. RESULTS: Oral administration of metformin (300 mg · kg(−1) · day(−1), 4 weeks) in streptozotocin-injected mice significantly blunted the diabetes-induced reduction of AMPK phosphorylation at Thr172. Metformin treatment also normalized acetylcholine-induced endothelial relaxation and increased the levels of GTPCH I and BH4. The administration of AICAR, an AMPK activator, or adenoviral overexpression of a constitutively active mutant of AMPK abolished the high-glucose–induced (30 mmol/l) reduction of GTPCH I, biopeterins, and BH4 but had no effect on GTPCH I mRNA. Furthermore, AICAR or overexpression of AMPK inhibited the high-glucose–enhanced 26S proteasome activity. Consistently, inhibition of the proteasome by MG132 abolished high-glucose–induced reduction of GTPCH I in human umbilical vein endothelial cells. Further, aortas isolated from AMPKα2(−/−) mice, which exhibited elevated 26S proteasome activity, had reduced levels of GTPCH I and BH4. Finally, either administration of MG132 or supplementation of l-sepiapterin normalized the impaired endothelium-dependent relaxation in aortas isolated from AMPKα2(−/−) mice. CONCLUSIONS: We conclude that AMPK activation normalizes vascular endothelial function by suppressing 26S proteasome-mediated GTPCH I degradation in diabetes. |
format | Text |
id | pubmed-2712774 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-27127742010-08-01 In Vivo Activation of AMP-Activated Protein Kinase Attenuates Diabetes-Enhanced Degradation of GTP Cyclohydrolase I Wang, Shuangxi Xu, Jian Song, Ping Viollet, Benoit Zou, Ming-Hui Diabetes Original Article OBJECTIVE: The activation of AMP-activated protein kinase (AMPK) has been reported to improve endothelial function. However, the targets of AMPK in endothelial cells remain poorly defined. The aim of this study was to test whether AMPK suppresses the degradation of GTP-cyclohydrolase (GTPCH I), a key event in vascular endothelial dysfunction in diabetes. RESEARCH DESIGN AND METHODS: Both human umbilical vein endothelial cells and aortas isolated from streptozotocin-injected diabetic mice were assayed for phospho-AMPK (Thr172), GTPCH I, tetrahydrobiopterin (BH4), and endothelial functions. RESULTS: Oral administration of metformin (300 mg · kg(−1) · day(−1), 4 weeks) in streptozotocin-injected mice significantly blunted the diabetes-induced reduction of AMPK phosphorylation at Thr172. Metformin treatment also normalized acetylcholine-induced endothelial relaxation and increased the levels of GTPCH I and BH4. The administration of AICAR, an AMPK activator, or adenoviral overexpression of a constitutively active mutant of AMPK abolished the high-glucose–induced (30 mmol/l) reduction of GTPCH I, biopeterins, and BH4 but had no effect on GTPCH I mRNA. Furthermore, AICAR or overexpression of AMPK inhibited the high-glucose–enhanced 26S proteasome activity. Consistently, inhibition of the proteasome by MG132 abolished high-glucose–induced reduction of GTPCH I in human umbilical vein endothelial cells. Further, aortas isolated from AMPKα2(−/−) mice, which exhibited elevated 26S proteasome activity, had reduced levels of GTPCH I and BH4. Finally, either administration of MG132 or supplementation of l-sepiapterin normalized the impaired endothelium-dependent relaxation in aortas isolated from AMPKα2(−/−) mice. CONCLUSIONS: We conclude that AMPK activation normalizes vascular endothelial function by suppressing 26S proteasome-mediated GTPCH I degradation in diabetes. American Diabetes Association 2009-08 2009-06-15 /pmc/articles/PMC2712774/ /pubmed/19528375 http://dx.doi.org/10.2337/db09-0267 Text en © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Original Article Wang, Shuangxi Xu, Jian Song, Ping Viollet, Benoit Zou, Ming-Hui In Vivo Activation of AMP-Activated Protein Kinase Attenuates Diabetes-Enhanced Degradation of GTP Cyclohydrolase I |
title | In Vivo Activation of AMP-Activated Protein Kinase Attenuates Diabetes-Enhanced Degradation of GTP Cyclohydrolase I |
title_full | In Vivo Activation of AMP-Activated Protein Kinase Attenuates Diabetes-Enhanced Degradation of GTP Cyclohydrolase I |
title_fullStr | In Vivo Activation of AMP-Activated Protein Kinase Attenuates Diabetes-Enhanced Degradation of GTP Cyclohydrolase I |
title_full_unstemmed | In Vivo Activation of AMP-Activated Protein Kinase Attenuates Diabetes-Enhanced Degradation of GTP Cyclohydrolase I |
title_short | In Vivo Activation of AMP-Activated Protein Kinase Attenuates Diabetes-Enhanced Degradation of GTP Cyclohydrolase I |
title_sort | in vivo activation of amp-activated protein kinase attenuates diabetes-enhanced degradation of gtp cyclohydrolase i |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712774/ https://www.ncbi.nlm.nih.gov/pubmed/19528375 http://dx.doi.org/10.2337/db09-0267 |
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