Abstract
IntroductionNiacin reduces vascular oxidative stress and down regulates inducible nitric oxide synthase, an enzyme mediating proatherosclerotic effects in part by increasing oxidative stress. Here, we evaluate whether Niacin reverses the redox sensitive migratory arrest of macrophages in response to oxidised(ox) LDL uptake.Material and MethodsMigration of RAW264.7 cells, a murine macrophage cell line and bone marrow derived macrophages from wildtype and iNOS knockout mice was quantified using a modified Boyden chamber. Unstimulated cells or cells preincubated with oxLDL or non-oxidised (n)LDL were treated with Nicotinic acid or Nicotinamide. Nitric oxide, peroxynitrite and ROS production were assessed using electron paramagnetic resonance (ESR). Additionally, flow cytometry analysis of apoptosis, fokal adhesion kinase (FAK), phalloidin, CD36, F4/80 macrophage marker and iNOS gene expression (PCR) were assessed.ResultsMigration of Nicotinic acid, Nicotinamide treated cells or unstimulated cells did not differ (P>0.05). oxLDL treatment significantly reduced migration vs. unstimulated cells (p<0.05). In contrast, migratory arrest in response to oxLDL treatment was reversed by co-incubation with Nicotinic acid and Nicotinamide. The oxLDL-induced peroxynitrite formation in RAW264.7 cells was abolished by Niacin and glutathion (GSH) oxidation was significantly reduced. However, nitric oxide (NO)- and reactive oxygen species (ROS) production induced by oxLDL were not affected by Niacin treatment of RAW264.7 cells. In addition, Nicotinic acid and Nicotinamide reduced actin polymerization, a marker for migratory arrest.DiscussionOur data shows that oxLDL induced inhibition of macrophage migration in vitro can be reversed by Niacin. Furthermore, Niacin reduces peroxynitite formation and improves antioxidant GSH.
Highlights
Niacin reduces vascular oxidative stress and down regulates inducible nitric oxide synthase, an enzyme mediating proatherosclerotic effects in part by increasing oxidative stress
The migration of cells treated with Nicotinic acid or Nicotinamide only, compared to the unstimulated group did not significantly differ. (P.0.05) (Fig. 1A, 1B) oxLDL treatment significantly reduced macrophage migration
In contrast to a large body of evidence regarding the mechanisms by which statins protect against cardiovascular disease, the cardioprotective mechanisms of Niacin are still not completely understood
Summary
Niacin reduces vascular oxidative stress and down regulates inducible nitric oxide synthase, an enzyme mediating proatherosclerotic effects in part by increasing oxidative stress. While most of the antiatherosclerotic effects are believed to result from its lipid modifying activity some evidence suggests that Nicotinic acid reduces cardiovascular mortality independent from its lipid modifying properties [4] In this respect, Niacin reduces plaque development independent of lipid lowering or HDL elevation in LDL receptor knockout mice [5]. Niacin reduces atherosclerosis in ApoE*3Leiden.CETP mice, a model closely resembling human lipoprotein metabolism, mainly by reducing non HDL cholesterol [6] Despite these positive results larger clinical trials like HPS2THRIVE failed to show an additional risk reduction when Niacin/Laropiprant was given to patients already reaching target cholesterol levels with statin treatment [7]. High risk patients intolerant to statins verify the need for alternative lipid lowering medications
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