Abstract
Nicotinic acid (NA) regresses atherosclerosis in human imaging studies and reduces atherosclerosis in mice, mediated by myeloid cells, independent of lipoproteins. Since GPR109A is expressed by human monocytes, we hypothesized that NA may drive cholesterol efflux from foam cells. In THP-1 cells NA suppressed LPS-induced mRNA transcription of MCP-1 by 76.6±12.2% (P<0.01) and TNFα by 56.1±11.5% (P<0.01), yet restored LPS-induced suppression of PPARγ transcription by 536.5±46.4% (P<0.001) and its downstream effector CD36 by 116.8±19.8% (P<0.01). Whilst direct PPARγ-agonism promoted cholesterol efflux from THP-1 derived foam cells by 37.7±3.1% (P<0.01) and stimulated transcription of LXRα by 87.9±9.5% (P<0.001) and ABCG1 by 101.2±15.5% (P<0.01), NA showed no effect in foam cells on either cholesterol efflux or key RCT genes transcription. Upon foam cell induction, NA lost its effect on PPARγ and cAMP pathways, since its receptor, GPR109A, was down-regulated by foam cell transformation. This observation was confirmed in explanted human carotid plaques. In conclusion, despite NA’s anti-inflammatory effect on human macrophages, it has no effect on foam cells in reverse cholesterol transport; due to GPR109A down-regulation.
Highlights
For over fifty years, nicotinic acid (NA) has been known to exert favourable effects on plasma lipoproteins [1]
As we have previously reported, NA treatment significantly attenuated this LPS-induced transcriptional up-regulation by 76.6612.2% for MCP-1 (P,0.01, n = 3 per group), and by 56.1611.5% for TNFa (P,0.01, n = 3 per group), confirming the anti-inflammatory effect of NA on basal non-foam cell macrophages
In order to elucidate why NA had no effect on reverse cholesterol transport (RCT) in foam cells, we investigated the effect of NA and GW1929 on genes in the PPARc-LXRa-ABC transporters pathway
Summary
Nicotinic acid (NA) has been known to exert favourable effects on plasma lipoproteins [1]. It reduces atherogenic lipoproteins LDL-c, VLDL-c, and Lp(a), and is the most efficacious drug currently available to raise plasma HDL-c (by up to 30%) [2]. The Coronary Drug Project [3] has shown benefits of NA in reducing cardiovascular events and mortality in patients with coronary heart disease, a finding supported by 2 recent metaanalyses [4,5]. One recent outcome trial was abandoned due to lack of efficacy [13]. A larger Phase III trial of a niacin/laropiprant combination did not reach its primary end point [14]
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