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  • br Introduction High dose niacin or

    2021-09-23


    Introduction High dose niacin, or nicotinic acid, has been used as an athero-protective drug for more than 50 years (Carlson, 2005, Offermanns, 2006). When taken in pharmacological doses (>1g/day), the nicotinic Oprozomib form of niacin modulates plasma lipid profiles including decreasing circulating total cholesterol, plasma LDL, triglycerides, and Lp(a), while increasing plasma HDL (reviewed in (Carlson, 2005, Montecucco et al., 2010) and inhibits lipolysis in adipose tissue (Carlson, 1963, Wahlberg and Walldius, 1993). Clinical trials assessing the cardiovascular benefits of niacin therapy, either alone or in combination with statins or fibrates, demonstrate that high-dose niacin treatment reduces nonfatal acute myocardial infarction (Brown et al., 1990, The Coronary Drug Project Research Group, 1975, Whitney et al., 2005), plaque progression (Blankenhorn et al., 1991, Blankenhorn et al., 1987, Brown et al., 1990, Lee et al., 2009a, Taylor et al., 2009), and overall mortality (Brown et al., 2001, Canner et al., 1986, Carlson and Rosenhamer, 1988, Taylor et al., 2009, The Coronary Drug Project Research Group, 1975, Whitney et al., 2005). Further, niacin therapy can reverse plaque progression in patients with peripheral artery disease and in fact, treatment induces regression in peripheral plaques (Lee et al., 2009b, Ost and Stenson, 1967). Identification of an orphan G-protein coupled receptor designated GPR109A, or HM74A in humans and PUMA-G in mice (Schaub et al. 2001), that specifically binds the nicotinic acid form of niacin with high affinity (Soga et al., 2003, Tunaru et al., 2003, Wise et al., 2003, Zhang et al., 2005), has shed light on possible mechanisms of niacin-mediated lipid modification (Tunaru et al., 2003, Zhang et al., 2005). These discoveries have also spurred a renewed interest in developing therapeutics that exploit the protection from cardiovascular disease that niacin induces. Emergent questions are whether the protective nature of niacin is solely due to its effects on raising plasma HDL and lowering LDL or whether it has other beneficial properties. The identification of GPR109A as a receptor for nicotinic acid opens up new approaches in addressing these questions. Humans express two closely related genes, HM74 and HM74A; however, only HM74A (GPR109A) binds niacin with high affinity (Wise et al., 2003, Zhang et al., 2005), and mice express only the high affinity GPR109A protein (Offermanns 2006). When niacin binds GPR109A, expressed primarily on mononuclear phagocytes, neutrophils, and adipocytes (Tunaru et al. 2003), an intense vasodilation in the skin, often called skin flushing, ensues (Benyo et al., 2005, Tunaru et al., 2003). Skin flushing is the primary reason for noncompliance and discontinuation during niacin therapy (Dunbar and Gelfand 2010), although there are a variety of symptoms that accompany the flush after ingestion of high-dose niacin. This has lead some investigators to describe the ancillary effects of niacin therapy as skin toxicity rather than skin flushing (Dunbar and Gelfand 2010). A biphasic model of niacin-induced skin flushing has been described (Hanson et al. 2010). The brief, first phase is dependent on Langerhans cells and their expression of GPR109A, cyclooxygenase (cox)-1 signaling, and prostaglandin D2 (PGD2) release that in turn promotes the vasodilation that characterizes the flush. A second, more sustained phase is mediated by GPR109A expression on keratinocytes, cox-2 signaling, and PGE2 release (Hanson et al. 2010). Considering that PGD2 release in the skin can inhibit the mobilization of antigen-presenting dendritic cells (DCs) to draining lymph nodes (Allan et al., 2006, Angeli et al., 2001), we hypothesized that skin flushing may lead to impaired DC migration. We reasoned that if niacin did inhibit DC migration, in turn, downstream adaptive immunity would likely be altered, and possibly in a way that confers clinical benefit, since atherosclerosis is partly a T cell-driven disease (Robertson and Hansson 2006). This consideration would be important to address in order to evaluate whether targeted pharmacological inhibition of skin flushing would simultaneously diminish any positive effects of niacin therapy. We therefore set out to examine whether skin flushing mediated by GPR109A altered DC trafficking from skin.