Nicotinic acid is an effective therapy in most forms of dyslipidemia and has been shown to reduce cardiovascular disease and death, yet its clinical use is limited by a prostaglandin D2 (PGD2)-mediated vasocutaneous flush. Both the cellular source and the exact mechanisms of nicotinic acid-induced activation of phospholipase A2 and subsequent PGD2 secretion are unknown. To better understand and prevent the niacin flush, and to define the molecular mechanisms involved, we have created an in vitro model of nicotinic acid-induced secretion of PGD2 using the human monoblastic leukemia cell line THP-1. THP-1 monocytes were transformed into macrophages upon exposure to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (16 nM, 24 hours). Transformed macrophages were exposed to nicotinic acid alone (0.1-3mM) or in the presence of positive and negative regulators of the arachidonic acid cascade. PGD2 secretion into the exposure media was measured using a competitive enzyme immunoassay specific for PGD2-methoxime. In the transformed macrophages, nicotinic acid caused a concentration and time-dependent increase in the secretion of PGD2. At 3mM, nicotinic acid increased PGD2 secretion as early as 5 minutes, and at 40 minutes resulted in a 3.2-fold increase compared to control (20.9 ± 5.2 pg/ml versus 6.5 ± 1.9 pg/ml; P ≤ 0.05). Pre-incubation of macrophages with the cyclo-oxygenase inhibitor aspirin (100 μM, 3 hours) completely prevented nicotinic acid-induced PGD2 secretion. Nicotinic acid's effects on PGD2 secretion were not dependent on extracellular calcium, and were additive to PGD2-secreting effects of the calcium ionophore A23187 (6 μM). Pre-incubation of macrophages with pertussis toxin (100 ng/ml, 3 hours) had no effect on nicotinic acid-induced PGD2 secretion. These data suggest that 1. Macrophages are a source of nicotinic acid-induced PGD2 secretion in humans. 2. Nicotinic acid acutely activates phospholipase A2 by a mechanism different that the calcium ionophore A23187. 3. Nicotinic acid-induced PGD2 release is not mediated by the pertussis-sensitive Gi-linked nicotinic acid receptor (HM74A). Further elucidation of the primary signaling event and secondary messenger systems involved in nicotinic acid-induced PGD2 secretion may not only result in alleviation of the niacin flush, but may also shed light on the role of alterations in lipid signaling molecules in mediating the metabolic effects of nicotinic acid.
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