The DDAH/ADMA/NOS pathway

doi:10.1016/S1567-5688(03)00032-1

Atherosclerosis Supplements

Volume 4, Issue 4, December 2003, Pages 33-40

https://doi.org/10.1016/S1567-5688(03)00032-1 Get rights and content

Abstract

An increasing number of reports in the literature indicate that endogenously produced inhibitors of nitric oxide synthase (NOS), particularly asymmetric dimethylarginine (ADMA) regulate nitric oxide generation in numerous disease states. Two dimethylarginine dimethylaminohydrolase (DDAH) enzymes metabolise ADMA. We and others have postulated that activity of DDAH is a key determinant of ADMA levels in vivo. This review summarises recent advances in the regulation and function of DDAH enzymes and its role in the regulation of nitric oxide generation.

Section snippets

Endogenous inhibitors of nitric oxide synthase

Free guanidino-methylated arginine residues occur endogenously as a result of proteolysis of post-translationally methylated tissue proteins [1]. The arginine analogues identified to date include N^G-monomethyl-l-arginine (l-NMMA), N^G,N^G-dimethyl-l-arginine (asymmetric dimethylarginine; ADMA) and N^G,N′^G-dimethyl-l-arginine (symmetric dimethylarginine; SDMA) (Fig. 1). The asymmetrically methylated arginine residues (l-NMMA and ADMA), but not the symmetrically methylated arginine (SDMA), are

How are methylarginines made?

Protein methylation is a post-translational modification involving addition of a methyl group to a polypeptide chain by enzymes termed protein methyltransferases (reviewed in [8], [9]). These enzymes utilise S-adenosylmethionine as methyl donors and catalyse a large number of modifications that can be divided into two groups. The first group of reactions modifies carboxyl groups to generate methyl esters. These reactions are generally reversible by the actions of protein methylesterases. They

When does free methylarginine appear?

An essential component of cell survival is protein degradation, and this is a major source of intracellular and plasma arginine and methylarginines. In the adult liver, for example, constitutive proteins are turned over at a rate of 40% per day [16]. In such tissues with high turnover rates, levels of free methylarginines liberated upon protein degradation (which are not re-incorporated into proteins) might be sufficiently high to inhibit NOS. In contrast, endothelial cells turn over very

Identification of DDAH

The isolation of appreciable quantities of ADMA and SDMA in human urine [1] led to the assumption that renal excretion was the only route for removal of free methylarginines. Indeed, on the assumption that neither re-incorporation nor catabolism occurred, ADMA and SDMA were used as markers of in vivo protein metabolism. However, investigation into the route of elimination of these amino acids showed that urinary excretion of SDMA was 30 times greater than that of either l-NMMA or ADMA in

ADMA as a risk factor for cardiovascular disease

ADMA is eliminated from the body by a combination of renal excretion and metabolism by DDAH. An increase in plasma ADMA levels was first reported in patients with renal failure [7], a condition in which cardiovascular disease is a major cause of death. In this disease, methylarginine excretion is diminished and both ADMA and SDMA accumulate in plasma. SDMA levels rise more than ADMA’s, probably because ADMA levels are reduced by DDAH activity. The rise in ADMA and subsequent inhibition of NO

Summary

It is becoming increasingly apparent that both the synthesis and metabolism of asymmetric methylarginine is highly regulated. Asymmetric methylarginines are endogenous inhibitors of all isoforms of NOS and are liberated upon proteolysis of proteins that have been methylated by PRMTs. Free methylarginine concentrations are determined in part by the enzymes that metabolise them, DDAH I and DDAH II, and regulation of NOS activity has been a central focus of DDAH studies. Given the pleiotropic

Acknowledgements

LT and JL were funded by British Heart Foundation Programme grant PG20007.

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The enzyme dimethylarginine dimethylaminohydrolase (DDAH) 1 metabolizes asymmetric dimethylarginine (ADMA), a critical endogenous cardiovascular risk factor. In the past two decades, there has been significant controversy about whether DDAH2, the other DDAH isoform, is also able to directly metabolize ADMA. There has been evidence that DDAH2 regulates several critical processes involved in cardiovascular and immune homeostasis. However, the molecular mechanisms underpinning these effects are unclear. In this opinion, we discuss the previous and current knowledge of ADMA metabolism by DDAH in light of a recent consortium study, which convincingly demonstrated that DDAH2 is not capable of metabolizing ADMA, unlike DDAH1. Thus, further research in this field is needed to uncover the molecular mechanisms of DDAH2 and its role in various disorders.
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Low concentrations of nitric oxide (NO) produced by constitutive NO synthase (cNOS) has been shown to suppress apoptosis in pancreatic β-cells. In the present study, the influence of asymmetric dimethylarginine (ADMA), the major endogenous inhibitor of NOS, on the apoptosis-suppressive effect of NO was investigated. The expression of dimethylarginine dimethylaminohydrolase 2 (DDAH2), an ADMA-metabolizing enzyme, in INS-1 β-cells and in mouse pancreatic islets was drastically reduced by in vitro exposure to high-concentration glucose (20 mM) and by in vivo treatment of mice with the insulin receptor blocker S661, which resulted in hyperglycemia, respectively. In line with this, a higher ADMA level was observed in INS-1 cells exposed to 20 mM glucose. The treatment of INS-1 cells with ADMA, similarly to with the NOS inhibitor N^G-nitro-L-arginine methyl ester, significantly facilitated 20 mM glucose-induced increase in cleaved caspase-3 protein expression. Furthermore, increased protein expression of cleaved caspase-3 and CHOP was observed in INS-1 cells with knockdown of DDAH2. These results suggest that ADMA accumulation through a decrease in DDAH2 expression in β-cells, which is induced under hyperglycemic conditions, facilitates β-cell apoptosis through suppression of cNOS-mediated NO production.
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Pulmonary fibrosis (PF) is a common but fatal disease that threatens human health worldwide. Developing effective diagnostic methods is of great importance for the early detection of PF in patients. In this study, bleomycin (BLM) was used in mice to mimic idiopathic pulmonary fibrosis (IPF). The exhaled breath of BLM-induced PF, PF plus DDAH1 overexpression, and healthy control mice were analyzed in real-time using a newly developed associative ionization time-of-flight mass spectrometry method (AI-TOFMS), which is uniquely sensitive, especially to oxygenated volatile organic compounds (VOCs). Multivariate data analyses and discriminant modeling analyses revealed that four exhaled compounds, i.e., acrolein, ethanol, nitric oxide, and ammonia, had a strong correlation with PF symptoms. An Orthogonal Partial Least Square Discriminant Analysis (OPLS-DA) score plot showed an excellent separation between these three groups. The area under the receiver operating characteristic (ROC) curve for these four compounds distinguished PF mice from healthy controls at 0.989. In addition, the degrees of acute inflammation and fibrosis were assessed with Hematoxylin and Eosin (H&E) staining and Masson's Trichrome staining. Finally, combined with pathological characteristics and mRNA expression levels, the formation of the above-mentioned volatile compounds was explored. The obtained experimental results indicated that these four breath compounds, acrolein, ethanol, nitric oxide, and ammonia, were potential exhaled biomarkers for pulmonary fibrosis.
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Asymmetric dimethyl arginine (ADMA) is an amino acid that acts as an endogenous competitive inhibitor of Nitric oxide synthase, leading to endothelial dysfunction (ED). The aim of this study was to evaluate the relationship between plasma ADMA (p-ADMA) level and ED in diabetic subjects with neuropathic foot ulcer (NFU), and the possible predictors of p-ADMA level.
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Several treatment strategies are nowadays available for erectile dysfunction (ED) patients. Currently, oral phosphodiesterase type 5 inhibitors (PDE5Is) are the first-line therapy for ED. However, they are effective in all treated cases with variable non-responsiveness. Many factors have been listed for this behavior, but the possibility of gene polymorphisms as an underlying cause has not been systematically investigated.
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The DDAH/ADMA/NOS pathway

Abstract

Section snippets

Endogenous inhibitors of nitric oxide synthase

How are methylarginines made?

When does free methylarginine appear?

Identification of DDAH

ADMA as a risk factor for cardiovascular disease

Summary

Acknowledgements

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Lancet

Curr. Opin. Cell Biol.

Trends Biochem. Sci.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Metabolism

Metabolism

Arch. Biochem. Biophys.

J. Biol. Chem.

Arch. Biochem. Biophys.

Kidney Int.

Biochim. Biophys. Acta

Genomics

Blood

J. Biol. Chem.

Kidney Int.

Kidney Int.

Lancet

J. Chromatogr. B. Biomed. Sci. Appl.

Am. J. Obstet. Gynecol.

Atherosclerosis

Biochem. Biophys. Res. Commun.

Life Sci.

Am. J. Cardiol.

Atherosclerosis

Neurosci. Lett.

J. Neurol. Sci.

Gastroenterology

Lancet

Neurosci. Lett.

Vascular endothelial cells synthesize nitric oxide from l-arginine

Nature

A specific inhibitor of nitric oxide formation from l-arginine attenuates endothelium-dependent relaxation

Br. J. Pharmacol.

Modulation of the vasodepressor actions of acetylcholine, bradykinin, substance P and endothelin in the rat by a specific inhibitor of nitric oxide formation

Br. J. Pharmacol.