Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
J Clin Invest. 2012 Apr;122(4):1459-68. doi: 10.1172/JCI59262. Epub 2012 Mar 12.
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.
烟酸在治疗血脂异常方面的临床应用受到有害副作用的限制，最常见的副作用是面部潮红。在小鼠中，烟酸引起的潮红是由 COX-1 依赖性 PGD₂和 PGE₂形成，然后是 COX-2 依赖性 PGE₂产生引起的。与此一致的是，当烟酸与 PGD₂受体 DP1 的拮抗剂联合使用时，可减轻烟酸引起的潮红。NSAID 介导的 COX-2 衍生的 PGI₂抑制对心血管有负面影响，但对 PGD₂的心血管生物学知之甚少。在这里，我们表明 PGD₂生物合成在人类血小板激活期间增强，尽管人类和小鼠之间血管 DP1的表达是保守的，但在小鼠中不存在血小板 DP1。尽管如此，DP1 缺失可增强小鼠的动脉瘤形成和对 Ang II 的高血压反应，并加速动脉粥样硬化和血栓形成。此外，人类中的 COX 抑制剂以及血小板耗竭、COX-1 敲低和 COX-2 缺失的小鼠，表明烟酸诱发血小板 COX-1 衍生的 PGD₂生物合成。最后，ADP 诱导的纤维蛋白原上的血小板扩散在经洗涤的人血小板中被烟酸增强，同时血栓素（Tx）形成增加。然而，在富含血小板的血浆中，Tx 和 PGD₂的形成均增加，扩散不那么明显，并且 DP1 激活抑制了扩散。因此，PGD₂与 PGI₂一样，可能作为对血栓形成和高血压刺激的稳态反应，并且在烟酸治疗期间对血小板可能具有特别重要的意义。
