Nitric Oxide Metabolism in Cardiovascular Disease

Nitric oxide (NO) is a gaseous signalling molecule central to vascular homeostasis, modulating vasodilation, platelet function and inflammation. Endothelial NO is synthesised from L-arginine by endothelial nitric oxide synthase (eNOS) and is finely regulated by endogenous inhibitors and cofactors. Among these, asymmetric dimethylarginine (ADMA) competes with L-arginine at the eNOS active site, reducing NO bioavailability and contributing to endothelial dysfunction—a hallmark of hypertension, atherosclerosis and heart failure. ADMA levels are controlled predominantly by dimethylarginine dimethylaminohydrolase (DDAH) isoforms, which hydrolyse ADMA to citrulline and dimethylamine. A growing body of work also recognises symmetric dimethylarginine (SDMA) as a modulator of NO pathways via indirect interference with L-arginine transport. Dysregulation of this metabolic network is implicated in increased vascular tone, inflammation and oxidative stress, promoting progression of cardiovascular disease. Recent advances have elucidated the molecular specificity of DDAH isoforms, the interplay between methylarginines and vascular reactivity, and the prognostic value of circulating methylarginines, paving the way for targeted therapies aimed at restoring NO balance.

Research from Nature Portfolio

Recent studies have resolved long-standing uncertainties regarding DDAH isoforms. A comprehensive consortium investigation combining computational models, cellular assays and murine experiments has demonstrated definitively that DDAH2 does not metabolise ADMA, clarifying that therapeutic strategies to lower ADMA should focus on DDAH1 activity or alternative pathways. This work shifts the paradigm away from DDAH2 as a direct ADMA-metabolising enzyme and highlights the need to explore DDAH2’s roles in mitochondrial dynamics, angiogenesis and immune modulation. By delineating isoform-specific functions, these findings refine targets for restoring NO bioavailability in cardiovascular disorders.

Nitric Oxide Metabolism in Cardiovascular Disease publication trend

The graph below shows the total number of articles in nitric oxide metabolism in cardiovascular disease across all publications each year (not limited to Nature Index journals).

Technical terms

Nitric oxide (NO): A diatomic free radical produced by endothelial cells that induces vasodilation and inhibits platelet aggregation.

Endothelial nitric oxide synthase (eNOS): The enzyme responsible for converting L-arginine to NO and citrulline within vascular endothelium.

L-arginine: A semi-essential amino acid that serves as the substrate for NO synthesis by eNOS.

Asymmetric dimethylarginine (ADMA): An endogenous methylated arginine derivative that competitively inhibits eNOS, reducing NO production.

Dimethylarginine dimethylaminohydrolase (DDAH): Enzymes (isoforms 1 and 2) that hydrolyse ADMA into citrulline and dimethylamine, regulating NO availability.

Symmetric dimethylarginine (SDMA): A methylated arginine isomer that impairs NO production indirectly by inhibiting cellular uptake of L-arginine.

References

1. A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase. Nature Communications (2023).
2. Asymmetric Dimethylarginine Enables Depolarizing Spikes and Vasospasm in Mesenteric and Coronary Resistance Arteries. Hypertension (2024).
3. SDMA as a marker and mediator in cerebrovascular disease. Clinical Science (2024).
4. Asymmetric and Symmetric Dimethylarginine as Risk Markers for Total Mortality and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis of Prospective Studies. PLOS ONE (2016).