Clinical Studies
Cigarette Smoking Is Associated With Increased Human Monocyte Adhesion to Endothelial Cells: Reversibility With Oral l-Arginine but Not Vitamin C

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Abstract

Objectives. This study sought to assess the effect of cigarette smoking on adhesion of human monocytes to human endothelial cells and to measure the effect of l-arginine and vitamin C supplementation on this interaction.

Background. Cigarette smoking has been associated with abnormal endothelial function and increased leukocyte adhesion to endothelium, both key early events in atherogenesis. Supplementation with both oral l-arginine (the physiologic substrate for nitric oxide) and vitamin C (an aqueous phase antioxidant) may improve endothelial function; however, their benefit in cigarette smokers is not known.

Methods. Serum was collected from eight smokers (mean [±SD] age 33 ± 5 years) with no other coronary risk factors and eight age- and gender-matched lifelong nonsmokers. The serum was added to confluent monolayers of human umbilical vein endothelial cells and incubated for 24 h. Human monocytes obtained by counterflow centrifugation elutriation were then added to these monolayers for 1 h, and adhesion then was measured by light microscopy. To assess reversibility, monocyte/endothelial cell adhesion was then measured for each subject 2 h after 2 g of oral vitamin C and 2 h after 7 g of oral l-arginine.

Results. In smokers compared with control subjects, monocyte/endothelial cell adhesion was increased (46.4 ± 4.5% vs. 27.0 ± 5.2%, p < 0.001), endothelial expression of intercellular adhesion molecule (ICAM)-1 was increased (0.31 ± 0.02 vs. 0.22 ± 0.03, p = 0.004), and vitamin C levels were reduced (33.7 ± 24.1 vs. 53.4 ± 11.5 μmol/liter, p = 0.028). After oral l-arginine, monocyte/endothelial cell adhesion was reduced in smokers (from 46.4 ± 4.5% to 35.1 ± 4.0%, p = 0.002), as was endothelial cell expression of ICAM-1 (from 0.31 ± 0.02 to 0.27 ± 0.01, p = 0.001). After vitamin C, there was no significant change in monocyte/endothelial cell adhesion or ICAM-1 expression from baseline in the smokers despite an increase in vitamin C levels (to 115 ± 7 μmol/liter).

Conclusions. Cigarette smoking is associated with increased monocyte–endothelial cell adhesion when endothelial cells are exposed to serum from healthy young adults. This abnormality is acutely reversible by oral l-arginine but not by vitamin C.

(J Am Coll Cardiol 1997;29:491–7)

Abbreviations

EDTA
ethylenediaminetetraacetic acid
ELISA
enzyme-linked immunosorbent assay
ICAM-1
intercellular adhesion molecule-1
HBSS
Hank’s balanced salt solution
HUVECs
human umbilical vein endothelial cells
IL-1beta
interleukin-1beta
IL-6
interleukin-6
RPMI
Roswell Park Memorial Institute
TNF-alpha
tumor necrosis factor-alpha
VCAM-1
vascular cell adhesion molecule-1

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This study was supported in part by grants from the National Health and Medical Research Council of Australia (NHMRC), Sydney and the National Heart Foundation of Australia (NHF), Sydney. Dr. Adams is supported by the NHF, Dr. Jessup by the NHMRC and Dr. Celermajer by The Medical Foundation of the University of Sydney, Sydney, Australia.