Abstract 18457: Acetylation of Asymmetric Dimethylarginine - a Novel Pathway of Clearance of Endogenous Methylarginines
Background: Epidemiological studies have shown that elevated levels of an endogenous inhibitor of nitric oxide synthases: asymmetric dimethylarginine (ADMA) are associated with cardiovascular diseases. ADMA can be hydrolysed by dimethylarginine dimethylaminohydrolase (DDAH) and metabolized through an alternative pathway by alanine:glyoxylate aminotransferase 2 (AGXT2). We and other have shown that ADMA can also be N-acetylated to form asymmetrical Nα-acetyldimethylarginine (Ac-ADMA) and excreted by the kidneys. The goal of the study was to characterize this novel pathway in physiological settings and in acute overload of ADMA in mice.
Results: We infused ADMA (250 μmol х kg-1 х d-1) in mice for three days using osmotic minipumps implanted intraperitoneally. Mice with saline infusion served as controls. Half of the mice underwent bilateral nephrectomy 24 hours before completion of the infusion, while the other half had a sham surgery. Infusion of ADMA led to increase in plasma ADMA levels both in the sham and nephrectomy groups (0.53 ± 0.07 μmol/l vs. 5.21 ± 3.25 μmol/l, and 0.63 ± 0.09 μmol/l vs. 5.32 ± 3.39 μmol/l). ADMA infusion resulted in significant increase in plasma levels of Ac-ADMA (1.35 ± 0.45 nmol/L vs. 4.77 ± 0.88 nmol/L) in the sham operated mice. Plasma Ac-ADMA levels were dramatically increased by nephrectomy (45.08 ± 9.25 nmol/L vs. 229.65 ± 91.30 nmol/L). Next we assayed tissue levels of Ac-ADMA in the unstressed healthy C57BL6 mice. The highest levels of Ac-ADMA were observed in the pancreas and in the small intestine as compared to the other organs (255.70 ±.63.34 pmol/g and 102.59 ± 9.22 pmol/g, respectively).
Conclusions: In this study we demonstrated that acute ADMA loading leads to elevation in Ac-ADMA, which is consistent with the hypothesis that Ac-ADMA is formed directly from ADMA in vivo. Dramatic increase in plasma Ac-ADMA levels after bilateral nephrectomy indicates that Ac-ADMA is predominantly eliminated via the kidneys. Increased Ac-ADMA levels in pancreas and intestine suggest that these organs might be the major sources of this metabolite. In a next step we want to identify the enzyme responsible for acetylation of ADMA and explore the clinical implications of this novel pathway of ADMA metabolism.
Author Disclosures: R.N. Rodionov: None. J. Martens-Lobenhoffer: None. S. Brilloff: None. N. Jarzebska: None. N. Weiss: None. S.M. Bode-Böger: None.
- © 2014 by American Heart Association, Inc.