Niacin inhibits vascular oxidative stress, redox-sensitive genes, and monocyte adhesion to human aortic endothelial cells

Abstract

In pharmacological doses, nicotinic acid (niacin) reduces myocardial infarction, stroke and atherosclerosis. The beneficial effects of niacin on lipoproteins are thought to mediate these effects. We hypothesized that niacin inhibits oxidative stress and redox-sensitive inflammatory genes that play a critical role in early atherogenesis. In cultured human aortic endothelial cells (HAEC), niacin increased nicotinamide adenine dinucleotide phosphate (NAD(P)H) levels by 54% and reduced glutathione (GSH) by 98%. Niacin inhibited: (a) angiotensin II (ANG II)-induced reactive oxygen species (ROS) production by 24–86%, (b) low density lipoprotein (LDL) oxidation by 60%, (c) tumor necrosis factor α (TNF-α)-induced NF-κB activation by 46%, vascular cell adhesion molecule-1 (VCAM-1) by 77–93%, monocyte chemotactic protein-1 (MCP-1) secretion by 34–124%, and (d) in a functional assay TNF-α-induced monocyte adhesion to HAEC (41–54%). These findings indicate for the first time that niacin inhibits vascular inflammation by decreasing endothelial ROS production and subsequent LDL oxidation and inflammatory cytokine production, key events involved in atherogenesis. Initial data presented herein support the novel concept that niacin has vascular anti-inflammatory and potentially anti-atherosclerotic properties independent of its effects on lipid regulation.

Introduction

Nicotinic acid (niacin) has been widely used clinically to regulate abnormalities in lipid/lipoprotein metabolism and in the treatment of atherosclerotic coronary heart disease (CHD; reviewed in Ref. [1]. In pharmacologic doses (1–3 g/day), niacin reduces plasma cholesterol, triglycerides, LDL, lipoprotein(a), and increases high-density lipoprotein (HDL) levels. Clinical studies have demonstrated that niacin alone or in combination can slow or reverse the progression of atherosclerosis, and reduce cardiovascular event rates and total mortality in patients with hypercholesterolemia and established atherosclerotic cardiovascular disease [1]. In combination therapy (e.g., statins), niacin can effect human coronary atherosclerosis regression and dramatically lower cardiovascular events by over 70% [2]. These unique beneficial effects of niacin on lipoproteins have been assumed to contribute to its anti-atherosclerotic properties. However, it is not clear whether the beneficial effects of niacin on atherosclerosis are completely explained by alterations in lipids.

Niacin, as a precursor for the synthesis of nicotinamide adenine dinucleotide (NAD⁺), increases cellular concentrations of NAD⁺[3]. Yan et al. have shown that the NAD⁺ precursors (e.g., niacin and nicotinamide) upregulate the expression of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway and the principal source of cellular reduced nicotinamide adenine dinucleotide phosphate (NADPH). Increased levels of NADPH decrease cellular reactive oxygen species (ROS) through regulating ROS-generating oxidases or by maintaining anti-oxidant enzymes such as catalase and glutathione reductase in active forms [4], [5]. Although niacin increases NAD⁺ levels and upregulates G6PD in Jurkat cell line (human T-cell lymphoma), the roles of niacin in vascular endothelial cell ROS formation, and subsequent oxidation of LDL and expression of oxidation-sensitive inflammatory genes involved in early atherosclerotic processes are not known. In this study, we hypothesized that niacin by increasing NAD(P)H levels increases the redox state of vascular endothelial cells resulting in decreased ROS formation, LDL oxidation, oxidation-responsive expression of vascular cell adhesion molecule-1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1), and, functionally, endothelial monocyte adhesion and infiltration, key early inflammatory events involved in atherosclerosis.