Correlation between increased nitric oxide production and markers of endothelial activation in systemic sclerosis: findings with the soluble adhesion molecules E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1

Arthritis Rheum. 2000 May;43(5):1085-93. doi: 10.1002/1529-0131(200005)43:5<1085::AID-ANR19>3.0.CO;2-7.


Objective: To determine the relationship between vascular function and the inflammatory response in systemic sclerosis (SSc), and to investigate whether production of endothelial-derived nitric oxide (NO) is disturbed in this disease.

Methods: We measured plasma nitrate, urinary excretion of both nitrate and cGMP, and soluble adhesion molecules of endothelial origin in patients with SSc and in age- and sex-matched controls and compared these levels between groups. Additionally, we performed correlation analysis to determine how these variables were related to one another. Plasma nitrate and 24-hour-urinary excretion of nitrate in patients and controls were measured after a 72-hour nitrate-free-diet, using a gas chromatography/mass spectrometric method. Soluble adhesion molecules intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1), and E-selectin and cytokines were measured by enzyme-linked immunosorbent assay. The expression of E-selectin was further investigated in skin biopsy specimens by immunoperoxidase staining, and the presence of inducible NO synthase by immunoblotting.

Results: Plasma nitrate and 24-hour-urinary-excretion of cGMP were significantly elevated in patients compared with controls, while 24-hour-urinary-excretion of nitrate tended to be elevated in SSc patients. Levels of sICAM-1, sVCAM-1, and sE-selectin were significantly elevated in the patients. Levels of plasma nitrate in the patients correlated significantly with levels of sVCAM-1 (P = 0.020) and sE-selectin (P = 0.018) and approached a significant correlation with sICAM-1 (P = 0.055), suggesting that activated endothelial cells may produce plasma nitrate.

Conclusion: NO synthesis is elevated in SSc patients, and the activated endothelial cell is a likely site of its production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biopsy
  • Cell Adhesion Molecules / metabolism
  • Cyclic GMP / urine
  • Cytokines / blood
  • E-Selectin / biosynthesis
  • E-Selectin / blood
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / physiology*
  • Female
  • Humans
  • Intercellular Adhesion Molecule-1 / blood
  • Male
  • Middle Aged
  • Nitrates / blood
  • Nitrates / urine
  • Nitric Oxide / biosynthesis*
  • Nitric Oxide Synthase / biosynthesis
  • Nitric Oxide Synthase Type II
  • Receptors, Cytokine / antagonists & inhibitors
  • Scleroderma, Systemic / metabolism*
  • Skin / chemistry
  • Skin / enzymology
  • Skin / pathology
  • Solubility
  • Vascular Cell Adhesion Molecule-1 / blood


  • Cell Adhesion Molecules
  • Cytokines
  • E-Selectin
  • Nitrates
  • Receptors, Cytokine
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • Nitric Oxide
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Cyclic GMP