Lead contributes to arterial intimal hyperplasia through nuclear factor erythroid 2-related factor-mediated endothelial interleukin 8 synthesis and subsequent invasion of smooth muscle cells.
OBJECTIVE
To validate the hypothesis that the toxic heavy metal lead (Pb) may be linked to cardiovascular diseases via the initiation of atherosclerosis, in vivo and in vitro studies were conducted.


RESULTS
During the human study part of this project, serum Pb levels of healthy young women were correlated to carotid intima-media thickness. Multivariate logistic regression analyses showed that increased serum Pb levels were significantly associated with an increased intima-media thickness (P=0.01; odds ratio per SD unit, 1.6 [95% CI, 1.1 to 2.4]). In vitro, Pb induced an increase in interleukin 8 production and secretion by vascular endothelial cells. Nuclear factor erythroid 2-related factor-2 is the crucial transcription factor involved in Pb-induced upregulation of interleukin 8. Endothelial cell-secreted interleukin 8 triggered intimal invasion of smooth muscle cells and enhanced intimal thickening in an arterial organ culture model. This phenomenon was further enhanced by Pb-increased elastin synthesis of smooth muscle cells.


CONCLUSIONS
Our data support the hypothesis that Pb is a novel, independent, and significant risk factor for intimal hyperplasia.
Zeller
Iris
I
Cardiac Surgery, Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna, Austria.
Knoflach
Michael
M
Seubert
Andreas
A
Kreutmayer
Simone B
SB
Stelzmüller
Marlies E
ME
Wallnoefer
Evelyn
E
Blunder
Stefan
S
Frotschnig
Sandra
S
Messner
Barbara
B
Willeit
Johann
J
Debbage
Paul
P
Wick
Georg
G
Kiechl
Stefan
S
Laufer
Günther
G
Bernhard
David
D
D000293:Adolescent; D002340:Carotid Artery Diseases / Q000097:blood / Q000000981:diagnostic imaging; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004549:Elastin / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D016209:Interleukin-8 / Q000378:metabolism*; D007854:Lead / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D016015:Logistic Models; D008323:Mammary Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016017:Odds Ratio; D009924:Organ Culture Techniques; D017534:Radial Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014463:Ultrasonography; D015854:Up-Regulation; D055815:Young Adult
C508606:CXCL8 protein, human; D006360:Heat-Shock Proteins; D016209:Interleukin-8; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D007854:Lead; C029891:lead chloride; D004549:Elastin