Myeloid Cell Prostaglandin E2 Receptor EP4 Modulates Cytokine Production but Not Atherogenesis in a Mouse Model of Type 1 Diabetes

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Abstract

Type 1 diabetes mellitus (T1DM) is associated with cardiovascular complications induced by atherosclerosis. Prostaglandin E ₂ (PGE ₂) is often raised in states of inflammation, including diabetes, and regulates inflammatory processes. In myeloid cells, a key cell type in atherosclerosis, PGE ₂ acts predominately through its Prostaglandin E Receptor 4 (EP4; Ptger4) to modulate inflammation. The effect of PGE ₂-mediated EP4 signaling specifically in myeloid cells on atherosclerosis in the presence and absence of diabetes is unknown. Because diabetes promotes atherosclerosis through increased arterial myeloid cell accumulation, we generated a myeloid cell-targeted EP4-deficient mouse model (EP4 ^M-/-) of T1DM-accelerated atherogenesis to investigate the relationship between myeloid cell EP4, inflammatory phenotypes of myeloid cells, and atherogenesis. Diabetic mice exhibited elevated plasma PGE metabolite levels and elevated Ptger4 mRNA in macrophages, as compared with non-diabetic littermates. PGE ₂ increased Il6, Il1b, Il23 and Ccr7 mRNA while reducing Tnfa mRNA through EP4 in isolated myeloid cells. Consistently, the stimulatory effect of diabetes on peritoneal macrophage Il6 was mediated by PGE ₂-EP4, while PGE ₂-EP4 suppressed the effect of diabetes on Tnfa in these cells. In addition, diabetes exerted effects independent of myeloid cell EP4, including a reduction in macrophage Ccr7 levels and increased early atherogenesis characterized by relative lesional macrophage accumulation. These studies suggest that this mouse model of T1DM is associated with increased myeloid cell PGE ₂-EP4 signaling, which is required for the stimulatory effect of diabetes on IL-6, markedly blunts the effect of diabetes on TNF-α and does not modulate diabetes-accelerated atherogenesis.

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Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia

Assam El-Osta, Daniella Brasacchio, Dachun Yao … (2008)

The current goal of diabetes therapy is to reduce time-averaged mean levels of glycemia, measured as HbA1c, to prevent diabetic complications. However, HbA1c only explains <25% of the variation in risk of developing complications. Because HbA1c does not correlate with glycemic variability when adjusted for mean blood glucose, we hypothesized that transient spikes of hyperglycemia may be an HbA1c–independent risk factor for diabetic complications. We show that transient hyperglycemia induces long-lasting activating epigenetic changes in the promoter of the nuclear factor κB (NF-κB) subunit p65 in aortic endothelial cells both in vitro and in nondiabetic mice, which cause increased p65 gene expression. Both the epigenetic changes and the gene expression changes persist for at least 6 d of subsequent normal glycemia, as do NF-κB–induced increases in monocyte chemoattractant protein 1 and vascular cell adhesion molecule 1 expression. Hyperglycemia-induced epigenetic changes and increased p65 expression are prevented by reducing mitochondrial superoxide production or superoxide-induced α-oxoaldehydes. These results highlight the dramatic and long-lasting effects that short-term hyperglycemic spikes can have on vascular cells and suggest that transient spikes of hyperglycemia may be an HbA1c–independent risk factor for diabetic complications.

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Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis.

Prabhakara R Nagareddy, Andrew J. Murphy, Roslynn A. Stirzaker … (2013)

Diabetes is a major risk factor for atherosclerosis. Although atherosclerosis is initiated by deposition of cholesterol-rich lipoproteins in the artery wall, the entry of inflammatory leukocytes into lesions fuels disease progression and impairs resolution. We show that diabetic mice have increased numbers of circulating neutrophils and Ly6-C(hi) monocytes, reflecting hyperglycemia-induced proliferation and expansion of bone marrow myeloid progenitors and release of monocytes into the circulation. Increased neutrophil production of S100A8/S100A9, and its subsequent interaction with the receptor for advanced glycation end products on common myeloid progenitor cells, leads to enhanced myelopoiesis. Treatment of hyperglycemia reduces monocytosis, entry of monocytes into atherosclerotic lesions, and promotes regression. In patients with type 1 diabetes, plasma S100A8/S100A9 levels correlate with leukocyte counts and coronary artery disease. Thus, hyperglycemia drives myelopoiesis and promotes atherogenesis in diabetes. Copyright © 2013 Elsevier Inc. All rights reserved.

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NADPH oxidase 1 plays a key role in diabetes mellitus-accelerated atherosclerosis.

Stephen P Gray, Elyse Di Marco, Jun Okabe … (2013)

In diabetes mellitus, vascular complications such as atherosclerosis are a major cause of death. The key underlying pathomechanisms are unclear. However, hyperglycemic oxidative stress derived from NADPH oxidase (Nox), the only known dedicated enzyme to generate reactive oxygen species appears to play a role. Here we identify the Nox1 isoform as playing a key and pharmacologically targetable role in the accelerated development of diabetic atherosclerosis. Human aortic endothelial cells exposed to hyperglycemic conditions showed increased expression of Nox1, oxidative stress, and proinflammatory markers in a Nox1-siRNA reversible manner. Similarly, the specific Nox inhibitor, GKT137831, prevented oxidative stress in response to hyperglycemia in human aortic endothelial cells. To examine these observations in vivo, we investigated the role of Nox1 on plaque development in apolipoprotein E-deficient mice 10 weeks after induction of diabetes mellitus. Deletion of Nox1, but not Nox4, had a profound antiatherosclerotic effect correlating with reduced reactive oxygen species formation, attenuation of chemokine expression, vascular adhesion of leukocytes, macrophage infiltration, and reduced expression of proinflammatory and profibrotic markers. Similarly, treatment of diabetic apolipoprotein E-deficient mice with GKT137831 attenuated atherosclerosis development. These studies identify a major pathological role for Nox1 and suggest that Nox1-dependent oxidative stress is a promising target for diabetic vasculopathies, including atherosclerosis.

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Author and article information

Contributors

Masanori Aikawa: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 28 June 2016

Publication date Collection: 2016

Volume: 11

Issue: 6

Electronic Location Identifier: e0158316

Affiliations

[1 ]Department of Medicine, UW Diabetes Institute, University of Washington, Seattle, WA 98109, United States of America

[2 ]Department of Pathology, UW Diabetes Institute, University of Washington, Seattle, WA 98109, United States of America

[3 ]Department of Medicine, Vanderbilt University, Nashville, TN 37212, United States of America

[4 ]Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, United States of America

Brigham and Women's Hospital, Harvard Medical School, UNITED STATES

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: SNV KEB. Performed the experiments: SNV FK SB. Analyzed the data: SNV JEK KEB. Contributed reagents/materials/analysis tools: RMB KIA. Wrote the paper: SNV JEK KEB.

* E-mail: bornf@ 123456u.washington.edu

Article

Publisher ID: PONE-D-16-05383

DOI: 10.1371/journal.pone.0158316

PMC ID: 4924840

PubMed ID: 27351842

SO-VID: 63bc6e0c-7841-436e-af99-f6d04ce9b8fd

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 5 February 2016

Date accepted : 14 June 2016

Page count

Figures: 7, Tables: 0, Pages: 20

Funding

Funded by: funder-id http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;

Award ID: R01HL062887