Direct effect of statins on homocysteine-induced endothelial adhesiveness: potential impact to human atherosclerosis.
BACKGROUND
Although homocysteine (HCY) is a risk factor for cardiovascular diseases, recent clinical trials failed to show the benefits by reducing plasma HCY. Alternative strategy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins, might be feasible. This study investigated HCY-induced endothelial adhesiveness with mononuclear cells (MNCs) from patients with coronary artery disease (CAD). The direct endothelial protective effects of statins were also examined.


METHODS
Circulating MNCs were isolated from 14 stable CAD patients and 7 age- and gender-matched healthy subjects. Superoxide production of MNCs was determined by Ultra-weak and luminol-enhanced chemiluminescence. Human aortic endothelial cells (HAECs) were used for endothelial adhesiveness to MNCs or U937 human monocytic cells. Endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were examined by Western blot.


RESULTS
Superoxide production of MNCs and plasma HCY and high-sensitive CRP levels were significantly increased in CAD patients than in healthy subjects. Stimulation with HCY enhanced the endothelial adhesiveness to MNCs from CAD patients or to U937 cells in a dose-dependent manner, whereas it was obscure with MNCs from healthy subjects. HCY stimulated endothelial VCAM-1 but not ICAM-1 expression in a dose-dependent manner. Monoclonal antibodies to VCAM-1 attenuated HCY-induced endothelial adhesiveness. Simvastatin or pravastatin significantly reduced HCY-induced VCAM-1 expression and endothelial adhesiveness to MNCs from CAD patients.


CONCLUSIONS
Circulating MNCs were activated in CAD patients, which was critical to HCY-induced endothelial adhesiveness. Statins could directly reduce HCY-induced endothelial-MNC adhesion via VCAM-1 inhibition, suggesting its potential implication in HCY-related atherosclerosis disease.
Lin
C P
CP
Institute of Public Health, National Yang-Ming University, Taipei, Taiwan.
Chen
Y H
YH
Lin
W T
WT
Leu
H B
HB
Liu
T Z
TZ
Huang
S L
SL
Chen
J W
JW
D000368:Aged; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D016022:Case-Control Studies; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003324:Coronary Artery Disease / Q000209:etiology* / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005260:Female; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017035:Pravastatin / Q000494:pharmacology*; D019821:Simvastatin / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D015815:Cell Adhesion Molecules; D006710:Homocysteine; D019821:Simvastatin; D017035:Pravastatin