Key Points
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Asymmetrically methylated arginines — principally asymmetric dimethylarginine (ADMA; that is, ω-NG,NG-asymmetric dimethylargenine) — are endogenously produced competitive inhibitors of nitric oxide synthase (NOS) enzymes. The concentration of asymmetric methylarginines is actively regulated in vivo by the action of dimethylarginine dimethylaminohydrolase (DDAH) enzymes that metabolize methylarginines to L-citrulline and methylamine.
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Modulation of DDAH activity in experimental models has demonstrated that endogenous inhibitors of NOS tonically inhibit the basal activity of NOS. Genetic or pharmacological disruption of DDAH activity impairs cardiovascular homeostasis in vivo, whereas overexpression of DDAH protects against cardiovascular disease in model systems.
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Genetic polymorphisms in human DDAH genes are associated with a variation in circulating ADMA levels and disease progression in several cardiovascular diseases including stroke, thrombosis and coronary artery disease. Increases in circulating plasma ADMA concentrations have been shown to strongly predict mortality in patients with end-stage renal disease.
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Pharmacological elevation of ADMA concentration has been suggested to be therapeutically useful in disease states in which excessive NO synthesis contributes to disease (for example, septic shock). Consistent with this proposition, genetic or pharmacological inhibition of DDAH has been shown to attenuate NO-dependent hypotension that is induced in animals with sepsis.
Abstract
Asymmetric dimethylarginine (ADMA) — a naturally occurring amino acid that is a product of protein breakdown — is released into the cytoplasm following the post-translational methylation of arginine residues within proteins and the subsequent proteolysis of these arginine-methylated proteins. ADMA inhibits all three isoforms of nitric oxide synthase and therefore has the potential to produce diverse biological effects, particularly in the cardiovascular system. In addition to its renal clearance, endogenously produced ADMA is metabolized to L-citrulline and dimethylamine by the dimethylarginine dimethylaminohydrolase (DDAH) enzymes. Pharmacological modification of DDAH has therefore been proposed as a mechanism for manipulating endogenous ADMA concentrations and regulating the production of nitric oxide in situations where alterations in nitric oxide signalling have been shown to contribute to pathophysiology. This Review describes the biology of ADMA and the potential therapeutic utility of manipulating DDAH activity.
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Acknowledgements
Research in the author's laboratories is funded by The Medical Research Council (J.L.), The Wellcome Trust (J.L.) and The British Heart Foundation (J.L. and M.N.).
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University College London, UK, has filed patents relating to therapeutic inhibition of dimethylarginine dimethylaminohydrolase. James Leiper is an inventor on these patent applications. Manasi Nandi does not declare any competing financial interests.
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FURTHER INFORMATION
Glossary
- K i
-
(Inhibitor dissociation constant).The Ki gives an indication of how potent an inhibitor is for a given target.
- ORF
-
(Open reading frame). The sequence of a gene that contains the protein coding sequence.
- IC50
-
The concentration of a compound that is required to achieve 50% inhibition of target activity.
- Associative studies
-
Studies in which the levels of biomarkers or risk factors are associated with pathology.
- 5/6 subtotal nephrectomy
-
Removal of five-sixths of renal mass to model renal insufficiency in animal models.
- eGFR
-
(Estimated glomerular filtration rate).The eGFR is used clinically to monitor renal function.
- Pulmonary arterial pressure
-
Blood pressure in the pulmonary artery — the blood vessel that transports blood from the right ventricle to the lung — that is determined, in part, by the resistance of the pulmonary vasculature.
- Right ventricular pressure
-
The blood pressure in the right ventricle of the heart. As the right ventricle supplies blood to the pulmonary circulation, right ventricular pressure reflects pulmonary vascular resistance.
- Pre-eclampsia
-
Hypertension induced by pregnancy.
- N-methyl-D-aspartate receptor
-
A glutamate receptor that is the predominant molecular device for controlling synaptic plasticity and memory function.
- Tumour grade
-
The developmental stage of a cancerous tumour.
- VEGF
-
(Vascular endothelial growth factor). A key signalling molecule that is responsible for the formation and function of blood vessels.
- Neovascularization
-
The formation of functional, perfused microvascular networks.
- Haploinsufficiency
-
Deletion of a single allele of any gene.
- IL-1β
-
(Interleukin-1β). A key cytokine involved in inflammatory responses.
- Response element
-
A sequence in the promoter of a gene that is bound by a transcription factor to modulate expression of the gene.
- Redox inactivation
-
The inactivation of enzymes by changes in the redox state of a cell. Typically, enzymes that contain active-site residues that are sensitive to the redox state of the cell are inactivated by oxidative or nitrosative stress.
- Tumour angiogenesis
-
The growth of new blood vessels into and around a growing tumour to maintain perfusion.
- Fluid resuscitation
-
The medical practice of replenishing bodily fluid that is lost as a consequence of vascular leakage during sepsis.
- Inotropic challenge
-
A dose of agent that increases the force of cardiac contraction
- Vasopressor challenge
-
A dose of a vasoconstrictive agent that is administered with the intention of raising blood pressure.
- Endotoxaemia
-
The presence of bacterial-derived endotoxins in the blood.
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Leiper, J., Nandi, M. The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis. Nat Rev Drug Discov 10, 277–291 (2011). https://doi.org/10.1038/nrd3358
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DOI: https://doi.org/10.1038/nrd3358
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