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. METHODS AND 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. CONCLUSION—Our data support the hypothesis that Pb is a novel, independent, and significant risk factor for intimal hyperplasia.