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Objective-Nicotinic acid (NA) treatment has been associated with benefits in atherosclerosis that are usually attributed to effects on plasma lipoproteins. The NA receptor GPR109A is expressed in monocytes and macrophages, suggesting a possible additional role for NA in modulating function of these immune cells. We hypothesize that NA has the potential to act directly on monocytes to alter mediators of inflammation that may contribute to its antiatherogenic effects in vivo. Methods and Results-In human monocytes activated by Toll-like receptor (TLR)-4 agonist lipopolysaccharide, NA reduced secretion of proinflammatory mediators: TNF-␣ (by 49.2Ϯ4.5%); interleukin-6 (by 56.2Ϯ2.8%), and monocyte chemoattractant protein-1 (by 43.2Ϯ3.1%) (PϽ0.01). In TLR2 agonist, heat-killed Listeria monocytogenes-activated human monocytes, NA reduced secretion of TNF-␣ (by 48.6Ϯ7.1%), interleukin-6 (by 60.9Ϯ1.6%), and monocyte chemoattractant protein-1 (by 59.3Ϯ5.3%) (PϽ0.01; nϭ7). Knockdown of GPR109A by siRNA resulted in a loss of this anti-inflammatory effect in THP-1 monocytes. However, inhibition of prostaglandin D 2 receptor by MK0524 or COX2 by NS398 did not alter the anti-inflammatory effects of NA observed in activated human monocytes. Preincubation of THP-1 monocytes with NA 0.1 mmol/L reduced phosphorylated IKK␤ by 42Ϯ2% (PϽ0.001) IKB-␣ by 54Ϯ14% (PϽ0.01). Accumulation of nuclear p65 NF-B in response to lipopolysaccharide treatment was also profoundly inhibited, by 89Ϯ1.3% (nϭ4; PϽ0.01). NA potently inhibited monocyte adhesion to activated HUVEC, and VCAM, mediated by the integrin, very late antigen 4. Monocyte chemotaxis was also significantly reduced (by 45.7Ϯ1.2%; PϽ0.001). Conclusion-NA displays a range of effects that are lipoprotein-independent and potentially antiatherogenic. These effects are mediated by GPR109A and are independent of prostaglandin pathways. They suggest a rationale for treatment with NA that is not dependent on levels of plasma cholesterol and possible applications beyond the treatment of dyslipidemia. (Arterioscler Thromb Vasc Biol. 2012;32:669-676.)Key Words: atherosclerosis Ⅲ cholesterol-lowering drugs Ⅲ macrophages Ⅲ receptors Ⅲ vascular biology I n patients with prior myocardial infarction, nicotinic acid (NA) reduces long-term mortality 1 and may confer additional antiatherogenic benefits when used in conjunction with statins. 2,3 These effects are generally attributed to favorable actions on the lipoprotein profile, which include LDL-cholesterol reduction and HDL-cholesterol elevation.In addition, NA reduces systemic markers of inflammation (eg, high-sensitivity C-reactive protein, monocyte chemoattractant protein-1 [MCP-1], and TNF-␣) and increases adiponectin, an adipokine with insulin sensitizing, antiatherogenic, and antiinflammatory properties. 2,4 These observations raise the possibility of additional nonlipoprotein-mediated effects of NA. The receptor for NA, GPR109A, is abundantly expressed in adipocytes, where it suppresses free fatty acid release 5 and has G-protein coupled rece...

Investigation of sequence variation in common inbred mouse strains has revealed a segmented pattern in which regions of high and low variant density are intermixed. Furthermore, it has been suggested that allelic strain distribution patterns also occur in well defined blocks and consequently could be used to map quantitative trait loci (QTL) in comparisons between inbred strains. We report a detailed analysis of polymorphism distribution in multiple inbred mouse strains over a 4.8-megabase region containing a QTL influencing anxiety. Our analysis indicates that it is only partly true that the genomes of inbred strains exist as a patchwork of segments of sequence identity and difference. We show that the definition of haplotype blocks is not robust and that methods for QTL mapping may fail if they assume a simple block-like structure.

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