title: Hyperglycemia enhances arsenic-induced platelet and megakaryocyte activation.
abstract: Low to moderate inorganic arsenic (iAs) exposure is independently associated with cardiovascular disease (CVD), particularly for patients with diabetes mellitus (DM). The mechanism of increased CVD risk from iAs exposure in DM has not been adequately characterized. We evaluated whether increasing concentrations of glucose enhance the effects of iAs on platelet and megakaryocyte activity, key steps in atherothrombosis.
  
  
  
  Healthy donor whole blood was prepared in a standard fashion and incubated with sodium arsenite in a range from 0 to 10 µM. iAs-induced platelet activation was assessed by platelet receptor CD62P (P-selectin) expression and monocyte-platelet and leukocyte-platelet aggregation (MPA and LPA, respectively) in the presence of increasing sodium arsenite and glucose concentrations. Megakaryocyte (Meg-01) cell adhesion and gene expression was assessed after incubation with or without iAs and increasing concentrations of D-glucose.
  
  
  
  Platelet activity markers increased significantly with 10 vs. 0 µM iAs (P < 0.05 for all) and with higher D-glucose concentrations. Platelet activity increased significantly following co incubation of 1 and 5 µM iAs concentrations with hyperglycemic D-glucose (P < 0.01 for both) but not after incubation with euglycemic D-glucose. Megakaryocyte adhesion was more pronounced after co incubation with iAs and hyperglycemic than euglycemic D-glucose, while gene expression increased significantly to iAs only after co incubation with hyperglycemic D-glucose.
  
  
  
  We demonstrate that glucose concentrations common in DM potentiate the effect of inorganic arsenic exposure on markers of platelet and megakaryocyte activity. Our results support recent observational cohort data that DM enhances the vasculotoxic effects of arsenic exposure, and suggest that activation of the platelet-megakaryocyte hemostatic axis is a pathway through which inorganic arsenic confers atherothrombotic risk, particularly for patients with DM.
authors.affiliation: Division of Cardiology and the Center for the Prevention of Cardiovascular Disease, Department of Medicine, New York University School of Medicine, TRB rm. 853, New York, NY, 10016, USA. Jonathan.Newman@nyumc.org.
authors.forename: Jonathan D
authors.identifier: 0000-0001-6855-7305
authors.initials: JD
authors.lastname: Newman
authors.affiliation: Department of Medicine, Marc and Ruti Bell Program in Vascular Biology and Disease, New York University Medical Center, New York, NY, USA.
authors.forename: Christina T
authors.initials: CT
authors.lastname: Echagarruga
authors.affiliation: Department of Medicine, Marc and Ruti Bell Program in Vascular Biology and Disease, New York University Medical Center, New York, NY, USA.
authors.forename: Yoscar M
authors.initials: YM
authors.lastname: Ogando
authors.affiliation: Department of Medicine, Marc and Ruti Bell Program in Vascular Biology and Disease, New York University Medical Center, New York, NY, USA.
authors.forename: Emilie
authors.initials: E
authors.lastname: Montenont
authors.affiliation: Departments of Medicine, Population Health and Environmental Medicine, New York University Medical Center, New York, NY, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Division of Cardiology and the Center for the Prevention of Cardiovascular Disease, Department of Medicine, New York University School of Medicine, TRB rm. 853, New York, NY, 10016, USA.|Department of Medicine, Marc and Ruti Bell Program in Vascular Biology and Disease, New York University Medical Center, New York, NY, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.affiliation: Division of Cardiology and the Center for the Prevention of Cardiovascular Disease, Department of Medicine, New York University School of Medicine, TRB rm. 853, New York, NY, 10016, USA.|Department of Medicine, Marc and Ruti Bell Program in Vascular Biology and Disease, New York University Medical Center, New York, NY, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Berger
mesh_terms: D001151:Arsenic / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006943:Hyperglycemia / Q000473:pathology*; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects*; D013917:Thrombin / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; D019007:P-Selectin; D013917:Thrombin; D001151:Arsenic
keywords: Atherothrombosis; Diabetes mellitus; Environmental exposures; Inorganic arsenic; Megakaryocyte adhesion; Platelet activity