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.
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.


CONCLUSIONS
NO synthesis is elevated in SSc patients, and the activated endothelial cell is a likely site of its production.
Andersen
G N
GN
University Hospital of Umeå, Sweden.
Caidahl
K
K
Kazzam
E
E
Petersson
A S
AS
Waldenström
A
A
Mincheva-Nilsson
L
L
Rantapää-Dahlqvist
S
S
D000368:Aged; D001706:Biopsy; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006152:Cyclic GMP / Q000652:urine; D016207:Cytokines / Q000097:blood; D019040:E-Selectin / Q000096:biosynthesis / Q000097:blood; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009566:Nitrates / Q000097:blood / Q000652:urine; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors; D012595:Scleroderma, Systemic / Q000378:metabolism*; D012867:Skin / Q000737:chemistry / Q000201:enzymology / Q000473:pathology; D012995:Solubility; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
D015815:Cell Adhesion Molecules; D016207:Cytokines; D019040:E-Selectin; D009566:Nitrates; D018121:Receptors, Cytokine; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D006152:Cyclic GMP