title: Nicotinic acid and DP1 blockade: studies in mouse models of atherosclerosis.
abstract: 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. 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.
authors.affiliation: Atherosclerosis, Merck Sharp & Dohme Corp., Rahway, NJ 07065, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Strack
authors.forename: Ester
authors.initials: E
authors.lastname: Carballo-Jane
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Wang
authors.forename: Jiyan
authors.initials: J
authors.lastname: Xue
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Ping
authors.forename: Lesley Ann
authors.initials: LA
authors.lastname: McNamara
authors.forename: Anil
authors.initials: A
authors.lastname: Thankappan
authors.forename: Olga
authors.initials: O
authors.lastname: Price
authors.forename: Michael
authors.initials: M
authors.lastname: Wolff
authors.forename: T J
authors.initials: TJ
authors.lastname: Wu
authors.forename: Douglas
authors.initials: D
authors.lastname: Kawka
authors.forename: Michele
authors.initials: M
authors.lastname: Mariano
authors.forename: Charlotte
authors.initials: C
authors.lastname: Burton
authors.forename: Ching H
authors.initials: CH
authors.lastname: Chang
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Menke
authors.forename: Silvi
authors.initials: S
authors.lastname: Luell
authors.forename: Emanuel I
authors.initials: EI
authors.lastname: Zycband
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Richard
authors.initials: R
authors.lastname: Raubertas
authors.forename: Carl P
authors.initials: CP
authors.lastname: Sparrow
authors.forename: Brian
authors.initials: B
authors.lastname: Hubbard
authors.forename: John
authors.initials: J
authors.lastname: Woods
authors.forename: Gary
authors.initials: G
authors.lastname: O'Neill
authors.forename: M Gerard
authors.initials: MG
authors.lastname: Waters
authors.forename: Ayesha
authors.initials: A
authors.lastname: Sitlani
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency; D002784:Cholesterol / Q000378:metabolism; D004347:Drug Interactions; D023381:Endpoint Determination; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D009525:Niacin / Q000494:pharmacology* / Q000627:therapeutic use; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics*; D011973:Receptors, LDL / Q000172:deficiency; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D011982:Receptors, Prostaglandin; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D009525:Niacin; D002784:Cholesterol; C036293:prostaglandin D2 receptor