Abstract 590: Loss of Myeloid Cell Prostaglandin E Receptor 4 Does Not Alter Diabetes-Accelerated Atherosclerosis in a Murine Model of Type 1 Diabetes
Diabetes is associated with an increased risk of cardiovascular disease, largely due to increased atherosclerosis. Our studies have suggested myeloid cell prostaglandin E2 (PGE2) production as a possible mediator of diabetes-accelerated atherosclerosis in a virally-induced mouse model of type 1 diabetes. Prostaglandin E Receptor 4 (EP4; Ptger4) is a major PGE2 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.
Thus, we generated a Ptger4flox/flox LysM-Cretg/tg mouse model. Peritoneal macrophages isolated from these myeloid cell EP4-deficient (EP4M-/-) mice expressed <90% Ptger4 mRNA compared to LysM-Cretg/tg controls (n=10; p<0.0001). To analyze the role of myeloid cell EP4 in diabetes-accelerated atherosclerosis, we transplanted bone marrow from EP4M-/- mice and littermate controls into lethally irradiated Ldlr-/- 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 EP4M-/- 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 EP4M-/- 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 PGE2. Pretreatment of the cells with PGE2 (10 nM) followed by LPS stimulation resulted in a significant reduction of Tnfa and Il6 mRNA compared to LPS alone, and this anti-inflammatory effect of PGE2 was completely blocked in EP4-deficient cells.
These results suggest that myeloid cell EP4 mediates anti-inflammatory actions of PGE2 but that it is not involved in diabetes-accelerated atherosclerosis.
Author Disclosures: S.N. Vallerie: None. F. Kramer: None. J.E. Kanter: None. S. Barnhart: None. R.M. Breyer: None. K.I. Andreasson: None. K.E. Bornfeldt: None.
- © 2015 by American Heart Association, Inc.