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 PGD&sub2; and PGE&sub2; followed by COX-2-dependent production of PGE&sub2;. Consistent with this, niacin-induced flushing in humans is attenuated when niacin is combined with an antagonist of the PGD&sub2; receptor DP1. NSAID-mediated suppression of COX-2-derived PGI&sub2; has negative cardiovascular consequences, yet little is known about the cardiovascular biology of PGD&sub2;. Here, we show that PGD&sub2; 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 PGD&sub2; 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 PGD&sub2; was increased, spreading was not as pronounced and was inhibited by DP1 activation. Thus, PGD&sub2;, like PGI&sub2;, may function as a homeostatic response to thrombogenic and hypertensive stimuli and may have particular relevance as a constraint on platelets during niacin therapy.