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Media type:
E-Article
Title:
Abstract 590: Loss of Myeloid Cell Prostaglandin E Receptor 4 Does Not Alter Diabetes-Accelerated Atherosclerosis in a Murine Model of Type 1 Diabetes
Contributor:
Vallerie, Sara N;
Kramer, Farah;
Kanter, Jenny E;
Barnhart, Shelley;
Breyer, Richard M;
Andreasson, Katrin I;
Bornfeldt, Karin E
Description:
<jats:p>
Diabetes is associated with an increased risk of cardiovascular disease, largely due to increased atherosclerosis. Our studies have suggested myeloid cell prostaglandin E
<jats:sub>2</jats:sub>
(PGE
<jats:sub>2</jats:sub>
) production as a possible mediator of diabetes-accelerated atherosclerosis in a virally-induced mouse model of type 1 diabetes. Prostaglandin E Receptor 4 (EP4;
<jats:italic>Ptger4</jats:italic>
) is a major PGE
<jats:sub>2</jats:sub>
receptor in myeloid cells. We hypothesized that generation of a mouse model of myeloid cell-targeted EP4-deficiency would allow us to test the role of myeloid EP4 in diabetes-accelerated atherosclerosis.
</jats:p>
<jats:p>
Thus, we generated a
<jats:italic>
Ptger4
<jats:sup>flox/flox</jats:sup>
LysM-Cre
<jats:sup>tg/tg</jats:sup>
</jats:italic>
mouse model. Peritoneal macrophages isolated from these myeloid cell EP4-deficient (EP4
<jats:sup>M-/-</jats:sup>
) mice expressed <90%
<jats:italic>Ptger4</jats:italic>
mRNA compared to
<jats:italic>
LysM-Cre
<jats:sup>tg/tg</jats:sup>
</jats:italic>
controls (n=10; p<0.0001). To analyze the role of myeloid cell EP4 in diabetes-accelerated atherosclerosis, we transplanted bone marrow from EP4
<jats:sup>M-/-</jats:sup>
mice and littermate controls into lethally irradiated
<jats:italic>
Ldlr
<jats:sup>-/-</jats:sup>
</jats:italic>
RIP-LCMV mice (the model of type 1 diabetes) and, after 7 weeks of recovery, induced diabetes by viral infection and fed the mice a low-fat semi-purified diet for an additional 12 weeks. Diabetic EP4
<jats:sup>M-/-</jats:sup>
mice had similar blood glucose (568 ± 15 vs. 569 ± 15 mg/dl), blood cholesterol (531 ± 29 vs. 510 ± 37 mg/dl), and plasma triglycerides (249 ± 49 vs. 247 ± 44 mg/dl) as diabetic controls (n=15 all groups; mean ± SEM). At the endpoint, aortas were harvested for lesion area quantification. Diabetic EP4
<jats:sup>M-/-</jats:sup>
and diabetic wild type mice had similar lesion area (1.9% ± 0.2 vs. 1.7% ± 0.2), which were both increased (p < 0.01; n=9-15) as compared to their non-diabetic controls. Additionally, we analyzed the role of EP4 in inflammatory activation of myeloid cells ex vivo. EP4-deficiency had no significant effect on basal or lipopolysaccharide (LPS)-induced inflammatory gene expression in the absence of PGE
<jats:sub>2</jats:sub>
. Pretreatment of the cells with PGE
<jats:sub>2</jats:sub>
(10 nM) followed by LPS stimulation resulted in a significant reduction of
<jats:italic>Tnfa</jats:italic>
and
<jats:italic>Il6</jats:italic>
mRNA compared to LPS alone, and this anti-inflammatory effect of PGE
<jats:sub>2</jats:sub>
was completely blocked in EP4-deficient cells.
</jats:p>
<jats:p>
These results suggest that myeloid cell EP4 mediates anti-inflammatory actions of PGE
<jats:sub>2</jats:sub>
but that it is not involved in diabetes-accelerated atherosclerosis.
</jats:p>