title: Niacin and biosynthesis of PGD₂by platelet COX-1 in mice and humans.
abstract: The clinical use of niacin to treat dyslipidemic conditions is limited by noxious side effects, most commonly facial flushing. In mice, niacin-induced flushing results from COX-1-dependent formation of PGD₂ and PGE₂ followed by COX-2-dependent production of PGE₂. Consistent with this, niacin-induced flushing in humans is attenuated when niacin is combined with an antagonist of the PGD₂ receptor DP1. NSAID-mediated suppression of COX-2-derived PGI₂ has negative cardiovascular consequences, yet little is known about the cardiovascular biology of PGD₂. Here, we show that PGD₂ biosynthesis is augmented during platelet activation in humans and, although vascular expression of DP1 is conserved between humans and mice, platelet DP1 is not present in mice. Despite this, DP1 deletion in mice augmented aneurysm formation and the hypertensive response to Ang II and accelerated atherogenesis and thrombogenesis. Furthermore, COX inhibitors in humans, as well as platelet depletion, COX-1 knockdown, and COX-2 deletion in mice, revealed that niacin evoked platelet COX-1-derived PGD₂ biosynthesis. Finally, ADP-induced spreading on fibrinogen was augmented by niacin in washed human platelets, coincident with increased thromboxane (Tx) formation. However, in platelet-rich plasma, where formation of both Tx and PGD₂ was increased, spreading was not as pronounced and was inhibited by DP1 activation. Thus, PGD₂, like PGI₂, may function as a homeostatic response to thrombogenic and hypertensive stimuli and may have particular relevance as a constraint on platelets during niacin therapy.
authors.affiliation: Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Song
authors.forename: Jane
authors.initials: J
authors.lastname: Stubbe
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ricciotti
authors.forename: Naji
authors.initials: N
authors.lastname: Alamuddin
authors.forename: Salam
authors.initials: S
authors.lastname: Ibrahim
authors.forename: Irene
authors.initials: I
authors.lastname: Crichton
authors.forename: Maxwell
authors.initials: M
authors.lastname: Prempeh
authors.forename: John A
authors.initials: JA
authors.lastname: Lawson
authors.forename: Robert L
authors.initials: RL
authors.lastname: Wilensky
authors.forename: Lars Melholt
authors.initials: LM
authors.lastname: Rasmussen
authors.forename: Ellen
authors.initials: E
authors.lastname: Puré
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000652:urine; D000244:Adenosine Diphosphate / Q000494:pharmacology; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000378:metabolism / Q000517:prevention & control; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D002341:Carotid Artery Thrombosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D051545:Cyclooxygenase 1 / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000293:injuries / Q000378:metabolism; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D015539:Platelet Activation / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015230:Prostaglandin D2 / Q000096:biosynthesis* / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000097:blood; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology; D011973:Receptors, LDL / Q000172:deficiency; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000097:blood; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D013928:Thromboxane A2 / Q000096:biosynthesis
chemical_list: D001057:Apolipoproteins E; D016861:Cyclooxygenase Inhibitors; C530636:HCAR2 protein, human; D008565:Membrane Proteins; D010975:Platelet Aggregation Inhibitors; D043562:Receptors, G-Protein-Coupled; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D011978:Receptors, Nicotinic; D011982:Receptors, Prostaglandin; C527097:prostanoid D receptor 1, mouse; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D000244:Adenosine Diphosphate; C028290:2,3-dinor-6-ketoprostaglandin F1alpha; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496512:Ptgs1 protein, mouse; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor