Abstract 19529: Transgenic Overexpression of Alanine-Glyoxylate Aminotransferase 2 in Mice Lowers Asymmetric Dimethylarginine and Improves Vasomotor Function
Introduction: ADMA (asymmetric dimethylarginine), an inhibitor of nitric oxide synthase, has been shown in various studies to be associated with the risk of cardiovascular diseases. There are two known pathways of ADMA metabolism: hydrolysis to citrulline by dimethylarginine dimethylaminohydrolases (DDAH) and transamination by alanine-glyoxylate aminotransferase 2 (AGXT2) with formation of asymmetric dimethylguanidino valeric acid (ADGV). The second one is poorly understood.
Hypothesis: The goal of our study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of systemic levels of ADMA and improvement of vasomotor function.
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. There were no developmental or phenotypic abnormalities in the TG animals. HPLC-MS/MS was used to generate biochemical data. Systemic ADMA levels were decreased by 15% (p<0.05) in the TG mice, whereas ADGV plasma levels were 6 times higher in comparison with wild-types littermates (p<0.001). Heart and lung of TG animals exhibited 2 times lower tissue ADMA content in comparison with wild type mice (p<0.05). TG mice demonstrated improved endothelium-dependent vasodilation (in response to acetylcholine) in aortic rings. The endothelium-independent relaxation (in response to sodium nitroprusside) was unchanged. There was no difference in mean arterial blood pressure measured by telemetry between the wild type and AGXT2 TG mice. In further experiments, we crossed the AGXT2 TG mice with DDAH1 KO mice and showed that upregulation of AGXT2 protects DDAH1 KO mice from elevation of plasma ADMA levels and restores the vasomotor response in aortic rings.
Conclusions: In this study we demonstrated that upregulation of AGXT2 leads to lowering of ADMA levels and improvement of endothelium-dependent relaxation of aortic rings in vivo. AGXT2 thereby may be a potential drug target for long-term reduction of systemic ADMA levels in cardiovascular pathologies.
Author Disclosures: R. Rodionov: None. D. Burdin: None. S. Brilloff: None. V. Todorov: None. N. Jarzebska: None. J. Martens-Lobenhoffer: None. A. Hofmann: None. H. Morawietz: None. A. Demyanov: None. K. Hilgers: None. N. Cordasic: None. J. Jacobi: None. R. Maas: None. Y. Chen: None. S.M. Bode-Böger: None. C.P. Hugo: None. B. Hohenstein: None. N. Weiss: None.
- © 2016 by American Heart Association, Inc.