Результаты исследований: Научные публикации в периодических изданиях › статья › Рецензирование
Overexpression of alanine-glyoxylate aminotransferase 2 protects from asymmetric dimethylarginine-induced endothelial dysfunction and aortic remodeling. / Rodionov, Roman N.; Jarzebska, Natalia; Burdin, Dmitrii; Todorov, Vladimir; Martens-Lobenhoffer, Jens; Hofmann, Anja; Kolouschek, Anne; Cordasic, Nada; Jacobi, Johannes; Rubets, Elena; Morawietz, Henning; O’Sullivan, John F.; Markov, Alexander G.; Bornstein, Stefan R.; Hilgers, Karl; Maas, Renke; Pfluecke, Christian; Chen, Ying Jie; Bode-Böger, Stefanie M.; Hugo, Christian P.M.; Hohenstein, Bernd; Weiss, Norbert.
в: Scientific Reports, Том 12, № 1, 9381, 12.2022.Результаты исследований: Научные публикации в периодических изданиях › статья › Рецензирование
}
TY - JOUR
T1 - Overexpression of alanine-glyoxylate aminotransferase 2 protects from asymmetric dimethylarginine-induced endothelial dysfunction and aortic remodeling
AU - Rodionov, Roman N.
AU - Jarzebska, Natalia
AU - Burdin, Dmitrii
AU - Todorov, Vladimir
AU - Martens-Lobenhoffer, Jens
AU - Hofmann, Anja
AU - Kolouschek, Anne
AU - Cordasic, Nada
AU - Jacobi, Johannes
AU - Rubets, Elena
AU - Morawietz, Henning
AU - O’Sullivan, John F.
AU - Markov, Alexander G.
AU - Bornstein, Stefan R.
AU - Hilgers, Karl
AU - Maas, Renke
AU - Pfluecke, Christian
AU - Chen, Ying Jie
AU - Bode-Böger, Stefanie M.
AU - Hugo, Christian P.M.
AU - Hohenstein, Bernd
AU - Weiss, Norbert
N1 - Rodionov, R.N., Jarzebska, N., Burdin, D. et al. Overexpression of alanine-glyoxylate aminotransferase 2 protects from asymmetric dimethylarginine-induced endothelial dysfunction and aortic remodeling. Sci Rep 12, 9381 (2022). https://doi.org/10.1038/s41598-022-13169-2
PY - 2022/12
Y1 - 2022/12
N2 - Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by alanine-glyoxylate aminotransferase 2 (AGXT2). Deletion of DDAH1 in mice leads to elevation of ADMA in plasma and increase in blood pressure, while overexpression of human DDAH1 is associated with a lower plasma ADMA concentration and protective cardiovascular effects. The possible role of alternative metabolism of ADMA by AGXT2 remains to be elucidated. 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 setting of DDAH1 deficiency. We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2. qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of asymmetric dimethylguanidino valeric acid (ADGV), the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling. Upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the setting of DDAH1 deficiency. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful.
AB - Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by alanine-glyoxylate aminotransferase 2 (AGXT2). Deletion of DDAH1 in mice leads to elevation of ADMA in plasma and increase in blood pressure, while overexpression of human DDAH1 is associated with a lower plasma ADMA concentration and protective cardiovascular effects. The possible role of alternative metabolism of ADMA by AGXT2 remains to be elucidated. 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 setting of DDAH1 deficiency. We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2. qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of asymmetric dimethylguanidino valeric acid (ADGV), the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling. Upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the setting of DDAH1 deficiency. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful.
KW - Amidohydrolases/genetics
KW - Animals
KW - Aorta/metabolism
KW - Arginine/analogs & derivatives
KW - Blood Pressure
KW - Mice
KW - Transaminases/genetics
KW - Vascular Diseases
UR - http://www.scopus.com/inward/record.url?scp=85131470400&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/246019e6-0f7a-3b0a-b9a7-71a4c48cec4c/
U2 - 10.1038/s41598-022-13169-2
DO - 10.1038/s41598-022-13169-2
M3 - Article
C2 - 35672381
AN - SCOPUS:85131470400
VL - 12
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 9381
ER -
ID: 99049548