Nicotinic acid and DP1 blockade: studies in mouse models of atherosclerosis

The use of nicotinic acid to treat dyslipidemia is limited by induction of a "flushing" response, mediated in part by the interaction of prostaglandin D-2 (PGD(2)) with its G-protein coupled receptor, DP1 (Ptgdr). The impact of DP1 blockade (genetic or pharmacologic) was assessed in experimental murine models of atherosclerosis. In Ptgdr(-/-) ApoE(-/-) mice versus ApoE(-/-) mice, both fed a high-fat diet, aortic cholesterol content was modestly higher (1.3- to 1.5-fold, P < 0.05) in Ptgdr(-/-) ApoE(-/-) mice at 16 and 24 weeks of age, but not at 32 weeks. In multiple ApoE(-/-) mouse studies, a DP1-specific antagonist, L-655, generally had a neutral to beneficial effect on aortic lipids in the presence or absence of nicotinic acid treatment. In a separate study, a modest increase in some atherosclerotic measures was observed with L-655 treatment in Ldlr(-/-) mice fed a high-fat diet for 8 weeks; however, this effect was not sustained for 16 or 24 weeks. In the same study, treatment with nicotinic acid alone generally decreased plasma and/or aortic lipids, and addition of L-655 did not negate those beneficial effects. jlr These studies demonstrate that inhibition of DP1, with or without nicotinic acid treatment, does not lead to consistent or sustained effects on plaque burden in mouse atherosclerotic models.-Strack, A. M., E. Carballo-Jane, S-p. Wang, J. Xue, X. Ping, L. A. McNamara, A. Thankappan, O. Price, M. Wolff, T. J. Wu, D. Kawka, M. Mariano, C. Burton, C. H. Chang, J. Chen, J. Menke, S. Luell, E. I. Zycband, X. Tong, R. Raubertas, C. P. Sparrow, B. Hubbard, J. Woods, G. O'Neill, M. G. Waters, and A. Sitlani. Nicotinic acid and DP1 blockade: studies in mouse models of atherosclerosis. J. Lipid Res. 2013. 54: 177-188.