Alanine-glyoxylate aminotransferase 2 overexpression protects from asymmetric dimethylarginine-induced endothelial dysfunction and aortic remodeling

Переведенное название: Сверхэкспрессия аланин-глиоксилат аминотрансферазы 2 защищает от вызванной асимметричным диметиларгинином эндотелиальной дисфункции и ремоделирования аорты

Александр Георгиевич Марков, Roman Rodionov, Natalia Jarzebska, Дмитрий Валерьевич Бурдин

Результат исследований: Научные публикации в периодических изданияхстатья

Выдержка

Rationale: Plasma concentrations of the endogenous inhibitor of nitric oxide synthases asymmetric dimethylarginine (ADMA) are associated with an increased risk of adverse outcome in cardiovascular disease (CVD). ADMA could be hydrolyzed to citrulline by dimethylarginine dimethylaminohydrolases (DDAHs), while downregulation of DDAHs is the major cause of ADMA elevation in CVD. ADMA can also be metabolized by alanine-glyoxylate aminotransferase 2 (AGXT2) with formation of asymmetric dimethylguanidino valeric acid (ADGV), however this pathway is poorly understood. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the settings of DDAH1 deficiency. Methods and Results: We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2 under control of the chicken beta actin (CAG) promoter. qPCR and Western Blot were used to confirm the ubiquitous expression of the transgene. HPLC-MS/MS was used to measure AGXT2 metabolites. Systemic ADMA levels were decreased by 15% (p<0.05) in the TG mice, whereas ADGV plasma levels were six times higher in comparison with wild type animals (p<0.001). Heart and lungs of TG animals exhibited 2 times lower tissue ADMA content in comparison with wild type littermates (p<0.05). We crossed the AGXT2 TG mice with DDAH1 knockout (KO) mice and showed that upregulation of AGXT2 protects DDAH1 KO mice from elevation of plasma ADMA levels, endothelial dysfunction and adverse aortic remodeling. Conclusion: In our study upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the settings of DDAH1 deficiency. We did not observe any adverse effects of chronic AGXT2 upregulation, suggesting that AGXT2 might be a potential drug target for long-term reduction of systemic ADMA levels in CVD. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful so far.
Язык оригиналаанглийский
Число страниц25
ЖурналArteriosclerosis, Thrombosis, and Vascular Biology
СостояниеОпубликовано - 2020

Предметные области Scopus

  • Биохимия, генетика и молекулярная биология (все)

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@article{a00c31a78df347968c9f1b5202843b8c,
title = "Alanine-glyoxylate aminotransferase 2 overexpression protects from asymmetric dimethylarginine-induced endothelial dysfunction and aortic remodeling",
abstract = "Rationale: Plasma concentrations of the endogenous inhibitor of nitric oxide synthases asymmetric dimethylarginine (ADMA) are associated with an increased risk of adverse outcome in cardiovascular disease (CVD). ADMA could be hydrolyzed to citrulline by dimethylarginine dimethylaminohydrolases (DDAHs), while downregulation of DDAHs is the major cause of ADMA elevation in CVD. ADMA can also be metabolized by alanine-glyoxylate aminotransferase 2 (AGXT2) with formation of asymmetric dimethylguanidino valeric acid (ADGV), however this pathway is poorly understood. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the settings of DDAH1 deficiency. Methods and Results: We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2 under control of the chicken beta actin (CAG) promoter. qPCR and Western Blot were used to confirm the ubiquitous expression of the transgene. HPLC-MS/MS was used to measure AGXT2 metabolites. Systemic ADMA levels were decreased by 15{\%} (p<0.05) in the TG mice, whereas ADGV plasma levels were six times higher in comparison with wild type animals (p<0.001). Heart and lungs of TG animals exhibited 2 times lower tissue ADMA content in comparison with wild type littermates (p<0.05). We crossed the AGXT2 TG mice with DDAH1 knockout (KO) mice and showed that upregulation of AGXT2 protects DDAH1 KO mice from elevation of plasma ADMA levels, endothelial dysfunction and adverse aortic remodeling. Conclusion: In our study upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the settings of DDAH1 deficiency. We did not observe any adverse effects of chronic AGXT2 upregulation, suggesting that AGXT2 might be a potential drug target for long-term reduction of systemic ADMA levels in CVD. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful so far.",
author = "Марков, {Александр Георгиевич} and Roman Rodionov and Natalia Jarzebska and Бурдин, {Дмитрий Валерьевич}",
year = "2020",
language = "English",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams and Wilkins",

}

Alanine-glyoxylate aminotransferase 2 overexpression protects from asymmetric dimethylarginine-induced endothelial dysfunction and aortic remodeling. / Марков, Александр Георгиевич; Rodionov, Roman; Jarzebska, Natalia ; Бурдин, Дмитрий Валерьевич.

В: Arteriosclerosis, Thrombosis, and Vascular Biology, 2020.

Результат исследований: Научные публикации в периодических изданияхстатья

TY - JOUR

T1 - Alanine-glyoxylate aminotransferase 2 overexpression protects from asymmetric dimethylarginine-induced endothelial dysfunction and aortic remodeling

AU - Марков, Александр Георгиевич

AU - Rodionov, Roman

AU - Jarzebska, Natalia

AU - Бурдин, Дмитрий Валерьевич

PY - 2020

Y1 - 2020

N2 - Rationale: Plasma concentrations of the endogenous inhibitor of nitric oxide synthases asymmetric dimethylarginine (ADMA) are associated with an increased risk of adverse outcome in cardiovascular disease (CVD). ADMA could be hydrolyzed to citrulline by dimethylarginine dimethylaminohydrolases (DDAHs), while downregulation of DDAHs is the major cause of ADMA elevation in CVD. ADMA can also be metabolized by alanine-glyoxylate aminotransferase 2 (AGXT2) with formation of asymmetric dimethylguanidino valeric acid (ADGV), however this pathway is poorly understood. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the settings of DDAH1 deficiency. Methods and Results: We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2 under control of the chicken beta actin (CAG) promoter. qPCR and Western Blot were used to confirm the ubiquitous expression of the transgene. HPLC-MS/MS was used to measure AGXT2 metabolites. Systemic ADMA levels were decreased by 15% (p<0.05) in the TG mice, whereas ADGV plasma levels were six times higher in comparison with wild type animals (p<0.001). Heart and lungs of TG animals exhibited 2 times lower tissue ADMA content in comparison with wild type littermates (p<0.05). We crossed the AGXT2 TG mice with DDAH1 knockout (KO) mice and showed that upregulation of AGXT2 protects DDAH1 KO mice from elevation of plasma ADMA levels, endothelial dysfunction and adverse aortic remodeling. Conclusion: In our study upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the settings of DDAH1 deficiency. We did not observe any adverse effects of chronic AGXT2 upregulation, suggesting that AGXT2 might be a potential drug target for long-term reduction of systemic ADMA levels in CVD. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful so far.

AB - Rationale: Plasma concentrations of the endogenous inhibitor of nitric oxide synthases asymmetric dimethylarginine (ADMA) are associated with an increased risk of adverse outcome in cardiovascular disease (CVD). ADMA could be hydrolyzed to citrulline by dimethylarginine dimethylaminohydrolases (DDAHs), while downregulation of DDAHs is the major cause of ADMA elevation in CVD. ADMA can also be metabolized by alanine-glyoxylate aminotransferase 2 (AGXT2) with formation of asymmetric dimethylguanidino valeric acid (ADGV), however this pathway is poorly understood. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the settings of DDAH1 deficiency. Methods and Results: We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2 under control of the chicken beta actin (CAG) promoter. qPCR and Western Blot were used to confirm the ubiquitous expression of the transgene. HPLC-MS/MS was used to measure AGXT2 metabolites. Systemic ADMA levels were decreased by 15% (p<0.05) in the TG mice, whereas ADGV plasma levels were six times higher in comparison with wild type animals (p<0.001). Heart and lungs of TG animals exhibited 2 times lower tissue ADMA content in comparison with wild type littermates (p<0.05). We crossed the AGXT2 TG mice with DDAH1 knockout (KO) mice and showed that upregulation of AGXT2 protects DDAH1 KO mice from elevation of plasma ADMA levels, endothelial dysfunction and adverse aortic remodeling. Conclusion: In our study upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the settings of DDAH1 deficiency. We did not observe any adverse effects of chronic AGXT2 upregulation, suggesting that AGXT2 might be a potential drug target for long-term reduction of systemic ADMA levels in CVD. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful so far.

M3 - Article

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

ER -