Abstract 373: Transgenic Overexpression of Alanine-glyoxylate Aminotransferase 2 Lowers Tissue Levels of Asymmetric Dimethylarginine and Improves Endothelial Function in Mouse Aortas
Introduction: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase, which has been proposed to play a direct role in the pathogenesis of cardiovascular disease. There are two enzymatic pathways for degradation of ADMA: hydrolysis to citrulline by dimethylarginine dimethylaminohydrolase (DDAH) and transamination by alanine-glyoxylate aminotransferase 2 (AGXT2) with formation of asymmetric dimethylguanidino valeric acid (ADGV). The first pathway is well characterized, whereas the physiological role of AGXT2 is still poorly understood. The goal of our study was to test the hypothesis that transgenic overexpression of AGXT2 would lead to lowering of systemic levels of ADMA and improved vasomotor function.
Methods and results: We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2 under control of the chicken beta actin (CAG) promoter. Ubiquitous overexpression of the transgene was confirmed by qPCR and Western Blot. TG animals had normal weight and no observed developmental abnormalities. Biochemical data were generated using HPLC-MS/MS. ADMA plasma levels in AGXT2 TG animals were decreased by 15% (p<0.05), whereas ADGV levels were 6 times higher in TG animals in comparison with wild-types (p<0.001). Lung and heart of TG animals exhibited 2 times lower tissue ADMA content in comparison with controls (p<0.05). Isolated aortic rings were used to estimate endothelium-dependent and -independent relaxation in response to acetylcholine (Ach) and sodium nitroprusside (SNP), respectively. Aortas from AGXT2 TG mice demonstrated an increase in maximal response to ACh (p<0.05). There was a similar relaxation in response to SNP in both groups.
Conclusions: Our findings show that upregulation of AGXT2 results in lower ADMA levels and improved endothelial-dependent relaxation in vivo. AGXT2 thereby may be a therapeutic target for long-term reduction of systemic ADMA levels and improvement of vascular function in vivo. This is especially important, because all the efforts to develop ADMA-lowering interventions by means of upregulation of DDAH have not been successful so far. Our data suggest that AGXT2 might be a promising drug target for cardiovascular pathologies associated with elevated ADMA levels.
Author Disclosures: R.N. Rodionov: None. D.V. Burdin: None. V. Todorov: None. S. Brilloff: None. N. Jarzebska: None. J. Martens-Lobenhoffer: None. A. Hofmann: None. H. Morawietz: None. A.V. Demyanov: None. R. Maas: None. S.M. Bode-Böger: None. C.P. Hugo: None. B. Hohenstein: None. N. Weiss: None.
- © 2015 by American Heart Association, Inc.