Tier 3 — preclinical

L-Arginine, Nitric Oxide, and Endothelial Dysfunction Underlying Atherosclerotic Cardiovascular Disease (ASCVD)

Shimabukuro M
Journal of Atherosclerosis and Thrombosis 2023 30(10):1311-1312

Bibliography

PubMed
PMID 37245961
PubMed Central
PMC10564653
DOI
10.5551/jat.ED235
Funding
Not stated (editorial commentary in J Atheroscler Thromb; no funding declaration provided).
Competing interests
None.

Study snapshot

DesignEditorial commentary (not a primary study)
ModelN/A - editorial discussing L-arginine/NO signaling in endothelial dysfunction and ASCVD
SampleN/A - editorial
InterventionN/A - editorial
DurationN/A - editorial
EndpointsL-arginine/L-ornithine ratio as marker of endothelial dysfunction; Long-term cardiovascular mortality prediction; eNOS/arginase balance and NO bioavailability

What the study showed, in plain terms

This short editorial explains why blood vessel lining (endothelial) health matters for heart disease and why the amino acid L-arginine sits at the center of it. L-arginine is the raw material the enzyme eNOS uses to make nitric oxide (NO), a molecule that keeps blood vessels relaxed, non-inflamed, and clot-resistant. When L-arginine is instead diverted by the enzyme arginase into L-ornithine and urea, less NO is made and the vessel lining becomes dysfunctional.

The author argues that the L-arginine/L-ornithine ratio - a simple blood measurement - could be a useful early warning sign of this NO-depleted state, and points to a companion study (Ishinoda et al., same issue) showing that a low ratio predicts long-term cardiovascular death. The commentary calls for more clinical work to confirm whether this ratio can be used as a practical biomarker for the onset of atherosclerotic cardiovascular disease.

Key findings

  • Endothelial dysfunction — the loss of nitric oxide-mediated vasoprotection — is an integrated marker of cardiovascular risk and is associated with cardiovascular events.
  • Nitric oxide, produced by endothelial nitric oxide synthase (eNOS) from L-arginine, inhibits vasoconstriction, vascular smooth muscle proliferation, leukocyte adhesion, and platelet aggregation.
  • The "arginine paradox" describes vascular endothelial dysfunction occurring even at normal circulating L-arginine levels, suggesting the substrate concentration alone does not determine eNOS output.
  • Ishinoda et al. (the accompanying original research paper) reported that a low L-arginine/L-ornithine ratio is associated with long-term cardiovascular mortality.
  • In sepsis and acute critical illness, altered cytokine states appear to activate CAT-2 (an inhibitor of L-arginine uptake) and deactivate CAT-1 (the transporter that brings L-arginine into cells) — likely shifting the balance toward inducible NOS and away from eNOS.
  • In the chronic phase, increased arginase activity diverts L-arginine and L-citrulline toward L-ornithine and urea, reducing substrate availability for eNOS-driven nitric oxide production.
  • The L-arginine/L-ornithine ratio is proposed as a potential integrated marker of this metabolic derangement, though the author explicitly notes clinical validation is still required.

What this study can and cannot tell us

This is a two-page invited editorial, not primary research and not a systematic review. It offers a mechanistic framing for a companion original article rather than new empirical data or a formal synthesis of evidence. Any conclusions drawn about the L-arginine/L-ornithine ratio as a biomarker rest almost entirely on the single accompanying observational study by Ishinoda et al. plus prior mechanistic literature cited briefly.

The editorial does not evaluate whether oral L-arginine supplementation improves the L-arginine/L-ornithine ratio, endothelial function, or cardiovascular outcomes in humans. It also does not address the well-documented mixed and sometimes negative findings for L-arginine supplementation in post-myocardial-infarction populations. Readers should not infer from this editorial that supplementation is a validated intervention for atherosclerotic cardiovascular disease.

The author states there are no conflicts of interest and no funding source is disclosed. As an editorial, the piece has not been subjected to the same peer-review process as an original research paper. Any clinical or supplementation decision-making should be anchored to the underlying primary literature it cites rather than the editorial's framing itself.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology