Arsenic Exposure Increases Monocyte Adhesion to the Vascular Endothelium, a Pro-Atherogenic Mechanism.
Epidemiological studies have shown that arsenic exposure increases atherosclerosis, but the mechanisms underlying this relationship are unknown. Monocytes, macrophages and platelets play an important role in the initiation of atherosclerosis. Circulating monocytes and macrophages bind to the activated vascular endothelium and migrate into the sub-endothelium, where they become lipid-laden foam cells. This process can be facilitated by platelets, which favour monocyte recruitment to the lesion. Thus, we assessed the effects of low-to-moderate arsenic exposure on monocyte adhesion to endothelial cells, platelet activation and platelet-monocyte interactions. We observed that arsenic induces human monocyte adhesion to endothelial cells in vitro. These findings were confirmed ex vivo using a murine organ culture system at concentrations as low as 10 ppb. We found that both cell types need to be exposed to arsenic to maximize monocyte adhesion to the endothelium. This adhesion process is specific to monocyte/endothelium interactions. Hence, no effect of arsenic on platelet activation or platelet/leukocyte interaction was observed. We found that arsenic increases adhesion of mononuclear cells via increased CD29 binding to VCAM-1, an adhesion molecule found on activated endothelial cells. Similar results were observed in vivo, where arsenic-exposed mice exhibit increased VCAM-1 expression on endothelial cells and increased CD29 on circulating monocytes. Interestingly, expression of adhesion molecules and increased binding can be inhibited by antioxidants in vitro and in vivo. Together, these data suggest that arsenic might enhance atherosclerosis by increasing monocyte adhesion to endothelial cells, a process that is inhibited by antioxidants.
Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada.
Maryse
M
Lemaire
Division of Experimental Medicine, Department of Medicine, Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada.
Luis Fernando
LF
Negro Silva
Division of Experimental Medicine, Department of Medicine, Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada; Department of Medicine, Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada.
Catherine A
CA
Lemarié
Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada.
Alicia M
AM
Bolt
Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada.
Manuel
M
Flores Molina
Department of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.
Regina M
RM
Krohn
Department of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.
Judit E
JE
Smits
Department of Medicine, Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada.
Stéphanie
S
Lehoux
Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada.
Koren K
KK
Mann
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001151:Arsenic / Q000009:adverse effects*; D050197:Atherosclerosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D002460:Cell Line; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004785:Environmental Pollutants / Q000009:adverse effects*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D009924:Organ Culture Techniques; D015539:Platelet Activation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000975:Antioxidants; D004785:Environmental Pollutants; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D001151:Arsenic