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

Abstract

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 (Pϭ0.01; 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. Key Words: Pb Ⅲ heavy metal Ⅲ endothelial Ⅲ Nrf2 Ⅲ interleukin Ⅲ smooth muscle cell Ⅲ invasion Ⅲ migration Ⅲ vascular Ⅲ pathophysiology Ⅲ risk factor Ⅲ intima media thickness Ⅲ atherosclerosis C ardiovascular and cerebrovascular diseases related to atherosclerosis are the leading cause of death in developed countries. 1 The identification of new risk factors is gaining more and more importance for disease prevention.The toxic heavy metal lead (Pb) is second on the Agency for Toxic Substances and Disease Registry's list of most hazardous substances. 2 Although the environmental burden in most countries has been declining because leaded gasoline is being phased out, 3 sources for Pb uptake are still ubiquitous. For example, Pb is emitted into the air through oil and coal combustion and nonferrous metal production. Pb pipes, Pbsoldered copper pipes, or Pb containing brass joints frequently can be found in older houses 4 and are still an important source for Pb uptake. In developing countries, the recycling of discarded Pb acid batteries under uncontrolled conditions poses a serious problem.The Pb that is absorbed reaches the bloodstream and binds to erythrocytes to an extent of approximately 99%; only 1% of total blood Pb can be found in plasma/serum. The half-life of Pb in blood and soft tissue is short (30 days). However, Pb is deposited in bone (in adults, 94% of the total body burden of Pb is contained in bones and teeth, with a half-life of 27 years 5 ). In addition, Barry 6 found that Pb accumulates in aortal tissue (with concentrations Յ60 mol/L) and that Pb levels in atherosclerotic vessels tend to be higher than in unaffected vessels.In general, blood Pb concentrations of greater than 10 g/dL (ie, Ͼ0.5 mol/L) are defined as Pb poisoning 7 ; however, because of the reported adverse health effects of Pb concentrations less than these values, ...

Cellular Defense Mechanisms against Lead Toxicity in the Vascular System

“…57) If lead substitutes for zinc in the metal-binding site of Keap1, Nrf2 will be activated. In fact, Korashy et 41) Consistent with these results, lead activates Nrf2 and its downstream proteins such as HO-1 and GCLM in HAEC (Fig. 2).…”

“…2). [38][39][40][41] Glutamate-cysteine ligase (GCL) is the rate-limiting enzyme in the glutathione biosynthesis pathway. GCL is a heterodimer consisting of a catalytic subunit (GCLC) and a modifier subunit (GCLM).…”

“…It has been reported that lead increases NQO1 in Hepa1c1c7 cells and HUVEC. [41][42][43] Because antioxidant and detoxifying proteins such as HO-1, GCLM, GSTA1, and NQO1 are regulated by transcription factor Nrf2, induction of these proteins by lead indicates that the Kelch-like ECH-associated protein 1-nuclear factor-erythroid 2-related factor 2 (Keap1-Nrf2) system contributes to the protective response against lead toxicity.…”

“…Besides the above-mentioned proteins, lead can induce metallothionein (MT), 44,45) heat shock protein 70 (HSP70), 41) pro-inflammatory protein cyclooxygenase-2 (COX-2), 46,47) pro-apoptotic protein Bax, 48,49) and glial fibrillary acidic protein (GFAP). 50) GFAP has been recently identified as a regulator of chaperone-mediated autophagy, 51) suggesting that the induction of GFAP serves to degrade aggregated proteins resulting from lead exposure.…”

Proliferation potential of human amniotic fluid stem cells differently responds to mercury and lead exposure

“…Interestingly, PbAc also has a proliferative effect on a variety of cells (rat and mouse kidney, rat liver, vascular smooth muscle, vascular endothelial and spleen cells) (Lu et al 2002;Zeller et al 2010). Therefore, it has been assumed that Pb may act as a tumor promoter.…”