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

Strack, Alison M ; Carballo-Jane, Ester ; Wang, Sheng-Ping ; Xue, Jiyan ; Ping, Xiaoli ; McNamara, Lesley Ann ; Thankappan, Anil ; Price, Olga ; Wolff, Michael ; Wu, T J ; Kawka, Douglas ; Mariano, Michele ; Burton, Charlotte ; Chang, Ching H ; Chen, Jing ; Menke, John ; Luell, Silvi ; Zycband, Emanuel I ; Tong, Xinchun ; Raubertas, Richard ; Sparrow, Carl P ; Hubbard, Brian ; Woods, John ; O'Neill, Gary ; Waters, M Gerard ; Sitlani, Ayesha

Journal of lipid research, 2013-01, Vol.54 (1), p.177-188 [Peer Reviewed Journal]

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Title:
Nicotinic acid and DP1 blockade: studies in mouse models of atherosclerosis
Author: Strack, Alison M ; Carballo-Jane, Ester ; Wang, Sheng-Ping ; Xue, Jiyan ; Ping, Xiaoli ; McNamara, Lesley Ann ; Thankappan, Anil ; Price, Olga ; Wolff, Michael ; Wu, T J ; Kawka, Douglas ; Mariano, Michele ; Burton, Charlotte ; Chang, Ching H ; Chen, Jing ; Menke, John ; Luell, Silvi ; Zycband, Emanuel I ; Tong, Xinchun ; Raubertas, Richard ; Sparrow, Carl P ; Hubbard, Brian ; Woods, John ; O'Neill, Gary ; Waters, M Gerard ; Sitlani, Ayesha
Description: 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.
Is Part Of: Journal of lipid research, 2013-01, Vol.54 (1), p.177-188
Publisher: United States: The American Society for Biochemistry and Molecular Biology
Identifier: ISSN: 0022-2275
EISSN: 1539-7262
DOI: 10.1194/jlr.M031344
PMID: 23103473
Subjects: Plaque, Atherosclerotic - genetics ; Apolipoproteins E - deficiency ; Humans ; Male ; Aorta - metabolism ; Niacin - pharmacology ; Receptors, Immunologic - antagonists & inhibitors ; Gene Knockdown Techniques ; Drug Interactions ; Niacin - therapeutic use ; Receptors, Prostaglandin - genetics ; Endpoint Determination ; Receptors, LDL - deficiency ; Female ; Receptors, Prostaglandin - deficiency ; Receptors, Prostaglandin - antagonists & inhibitors ; Plaque, Atherosclerotic - metabolism ; Receptors, Thromboxane A2, Prostaglandin H2 - metabolism ; Aorta - drug effects ; Receptors, Immunologic - deficiency ; Cholesterol - metabolism ; Animals ; Mice ; Plaque, Atherosclerotic - drug therapy ; Receptors, Immunologic - genetics ; Index Medicus ; atherosclerosis model ; dyslipidemia ; DP1 antagonist
Language: English

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

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