Hyperglycemia enhances arsenic-induced platelet and megakaryocyte activation

Jonathan D. Newman; Christina T. Echagarruga; Yoscar M. Ogando; Emilie Montenont; Yu Chen; Edward A. Fisher; Jeffrey S. Berger

doi:10.1186/s12967-017-1148-1

Hyperglycemia enhances arsenic-induced platelet and megakaryocyte activation

Jonathan D. Newman, Christina T. Echagarruga, Yoscar M. Ogando, Emilie Montenont, Yu Chen, Edward A. Fisher, Jeffrey S. Berger

Urban Initiative

Research output: Contribution to journal › Article › peer-review

Abstract

Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

Original language	English (US)
Article number	55
Journal	Journal of Translational Medicine
Volume	15
Issue number	1
DOIs	https://doi.org/10.1186/s12967-017-1148-1
State	Published - Mar 6 2017

Keywords

Atherothrombosis
Diabetes mellitus
Environmental exposures
Inorganic arsenic
Megakaryocyte adhesion
Platelet activity

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1186/s12967-017-1148-1

Cite this

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title = "Hyperglycemia enhances arsenic-induced platelet and megakaryocyte activation",

abstract = "Objective: 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. Methods: 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. Results: 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. Conclusion: 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.",

keywords = "Atherothrombosis, Diabetes mellitus, Environmental exposures, Inorganic arsenic, Megakaryocyte adhesion, Platelet activity",

author = "Newman, {Jonathan D.} and Echagarruga, {Christina T.} and Ogando, {Yoscar M.} and Emilie Montenont and Yu Chen and Fisher, {Edward A.} and Berger, {Jeffrey S.}",

note = "Funding Information: This study was funded by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) of the National Institute of Health (NIH, U24DK076169-09, subcontract 25732-60). Dr. Newman was partially funded by the National Heart, Lung, and Blood Institute (NHLBI) of the NIH (K23HL125991) and the American Heart Association Mentored Clinical and Population Research Award (15MCPRP24480132). Dr. Berger was partially funded by the NHLBI of the NIH (HL114978). Funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the article. Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = mar,

day = "6",

doi = "10.1186/s12967-017-1148-1",

language = "English (US)",

volume = "15",

journal = "Journal of Translational Medicine",

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TY - JOUR

T1 - Hyperglycemia enhances arsenic-induced platelet and megakaryocyte activation

AU - Newman, Jonathan D.

AU - Echagarruga, Christina T.

AU - Ogando, Yoscar M.

AU - Montenont, Emilie

AU - Chen, Yu

AU - Fisher, Edward A.

AU - Berger, Jeffrey S.

N1 - Funding Information: This study was funded by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) of the National Institute of Health (NIH, U24DK076169-09, subcontract 25732-60). Dr. Newman was partially funded by the National Heart, Lung, and Blood Institute (NHLBI) of the NIH (K23HL125991) and the American Heart Association Mentored Clinical and Population Research Award (15MCPRP24480132). Dr. Berger was partially funded by the NHLBI of the NIH (HL114978). Funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the article. Publisher Copyright: © 2017 The Author(s).

PY - 2017/3/6

Y1 - 2017/3/6

N2 - Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

AB - Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

KW - Atherothrombosis

KW - Diabetes mellitus

KW - Environmental exposures

KW - Inorganic arsenic

KW - Megakaryocyte adhesion

KW - Platelet activity

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Hyperglycemia enhances arsenic-induced platelet and megakaryocyte activation

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