Abstract 23242: Impact of Niacin and DP1 Blockade in Mouse Models of Atherosclerosis
Nicotinic acid is used clinically for treatment of dyslipidemia. A major limitation of the use of niacin is the induction of a “flushing” response, which is mediated in part by the interaction of prostaglandin D2 (PGD2) with its G-protein coupled receptor DP1. To understand the role of DP1 on niacin effects, DP1 blockade (genetic or pharmacological) was assessed on experimental murine models of atherosclerosis. DP1-/- mice were crossed with the Apoe-/- mouse, a mouse prone to atherosclerotic lesions, and development of plaque burden was assessed following 16, 24, and 32 weeks. Aortic cholesterol content was significantly higher, by 1.3-1.5 fold, in DP1-/- Apoe-/- mice vs Apoe-/- mice at the 16 and 24 weeks, but not at 32 weeks. An additional objective was to assess the effects of a DP1 antagonist on the lipid effects of niacin in both Apoe-/- and Ldlr-/- mouse models. DP1 antagonist L-655 was employed for pharmacological blockade because it is selective for murine DP1 over the thromboxane A2 (TxA2) receptor (TP) in both in vitro binding and in vivo pharmacodynamic assays. In multiple Apoe-/- mouse studies, L-655 had a neutral to beneficial effect on aortic lipids in the presence or absence of niacin treatment. Niacin (3% admixed in food) decreased aortic cholesterol by 22%, no effects were observed with L-655 at 30 or 300 ppm, and combination of niacin and L-655 resulted in decreases of 26% and 25%, at the two L-655 doses. In Ldlr-/- mice, the time course of the effects of L-655 alone on measures of atherosclerosis, including en face staining of the aorta and cross-sectional histological analyses of plaque composition, was assessed. Similar time dependent increases in atherosclerotic measures were observed with time in both vehicle and L-655 treated mice. At an 8 week, but not 16 or 24 week time points, higher measures of biochemical and histological measures were observed with L-655 treatment. In the same study, treatment with niacin alone tended to decrease plasma and/or aortic lipids, and addition of L-655 did not significantly reduce those effects. These studies demonstrate that inhibition of DP1, genetically or pharmacologically, has modest, transient effects on plaque burden but is without impact on the niacin effects in multiple mouse atherosclerotic models.
- © 2010 by American Heart Association, Inc.