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Effects of niacin on atherosclerosis and vascular function.

ABSTRACT: Niacin has been used for more than 50 years in the management of atherosclerosis and is associated with improved patient outcomes. The routine use of niacin has been superseded in recent years with the advent of newer lipid-modulating interventions. Recently, however, there has been a renewed interest in its use due to the appreciation of its many beneficial effects on atherosclerosis and endothelial function, both 'lipid-targeted' and 'pleiotropic'. This review will consider the effects of niacin in the setting of clinical trials and will critically evaluate proposed mechanisms of action.The identification of the GPR109A receptor has promoted a greater insight into niacin's mechanism of action, with demonstrated beneficial effects on endothelial function and inflammation, in addition to its lipid modulation role.Whether niacin itself is used routinely in the future will depend on the outcomes of two large outcome trials (AIM-HIGH and HPS2-THRIVE). In the future, however, with even better understanding of niacin pharmacology, new drugs may be able to be engineered to capture aspects of niacin that capitalize on the benefits more specifically and also more selectively, to avoid troublesome side-effects.

SUBMITTER: Ruparelia N

PROVIDER: S-EPMC3145140 | biostudies-other | 2011 Jan

REPOSITORIES: biostudies-other

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Effects of niacin on atherosclerosis and vascular function.

Ruparelia Neil N Digby Janet E JE Choudhury Robin P RP

Current opinion in cardiology 20110101 1

<h4>Purpose of review</h4>Niacin has been used for more than 50 years in the management of atherosclerosis and is associated with improved patient outcomes. The routine use of niacin has been superseded in recent years with the advent of newer lipid-modulating interventions. Recently, however, there has been a renewed interest in its use due to the appreciation of its many beneficial effects on atherosclerosis and endothelial function, both 'lipid-targeted' and 'pleiotropic'. This review will co ...[more]

PMID: 21045681

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Project description:ObjectiveNiacin potently lowers triglycerides, mildly decreases LDL-cholesterol, and largely increases HDL-cholesterol. Despite evidence for an atheroprotective effect of niacin from previous small clinical studies, the large outcome trials, AIM-HIGH and HPS2-THRIVE did not reveal additional beneficial effects of niacin (alone or in combination with laropiprant) on top of statin treatment. We aimed to address this apparent discrepancy by investigating the effects of niacin without and with simvastatin on atherosclerosis development and determine the underlying mechanisms, in APOE*3Leiden.CETP mice, a model for familial dysbetalipoproteinemia (FD).Approach and resultsMice were fed a western-type diet containing cholesterol without or with niacin (120 mg/kg/day), simvastatin (36 mg/kg/day) or their combination for 18 weeks. Similarly as in FD patients, niacin reduced total cholesterol by -39% and triglycerides by -50%, (both P<0.001). Simvastatin and the combination reduced total cholesterol (-30%; -55%, P<0.001) where the combination revealed a greater reduction compared to simvastatin (-36%, P<0.001). Niacin decreased total cholesterol and triglycerides primarily by increasing VLDL clearance. Niacin increased HDL-cholesterol (+28%, P<0.01) and mildly increased reverse cholesterol transport. All treatments reduced monocyte adhesion to the endothelium (-46%; -47%, P<0.01; -53%, P<0.001), atherosclerotic lesion area (-78%; -49%, P<0.01; -87%, P<0.001) and severity. Compared to simvastatin, the combination increased plaque stability index [(SMC+collagen)/macrophages] (3-fold, P<0.01). Niacin and the combination reduced T cells in the aortic root (-71%, P<0.01; -81%, P<0.001). Lesion area was strongly predicted by nonHDL-cholesterol (R(2)?=?0.69, P<0.001) and to a much lesser extent by HDL-cholesterol (R(2)?=?0.20, P<0.001).ConclusionNiacin decreases atherosclerosis development mainly by reducing nonHDL-cholesterol with modest HDL-cholesterol-raising and additional anti-inflammatory effects. The additive effect of niacin on top of simvastatin is mostly dependent on its nonHDL-cholesterol-lowering capacities. These data suggest that clinical beneficial effects of niacin are largely dependent on its ability to lower LDL-cholesterol on top of concomitant lipid-lowering therapy.

Project description:BACKGROUND:Neopterin, a metabolite of GTP, is produced by activated macrophages and is abundantly expressed within atherosclerotic lesions in human aorta and carotid and coronary arteries. We aimed to clarify the influence of neopterin on both vascular inflammation and atherosclerosis, as neither effect had been fully assessed. METHODS AND RESULTS:We investigated neopterin expression in coronary artery lesions and plasma from patients with coronary artery disease. We assessed the atheroprotective effects of neopterin in vitro using human aortic endothelial cells, human monocyte-derived macrophages, and human aortic smooth muscle cells. In vivo experiments included a study of aortic lesions in apolipoprotein E-deficient mice. Neopterin expression in coronary artery lesions and plasma was markedly increased in patients with versus without coronary artery disease. In human aortic endothelial cells, neopterin reduced proliferation and TNF-? (tumor necrosis factor ?)-induced upregulation of MCP-1 (monocyte chemotactic protein 1), ICAM-1 (intercellular adhesion molecule 1), and VCAM-1 (vascular cell adhesion molecule 1). Neopterin attenuated TNF-?-induced monocyte adhesion to human aortic endothelial cells and the inflammatory macrophage phenotype via NF-?B (nuclear factor-?B) downregulation. Neopterin suppressed oxidized low-density lipoprotein-induced foam cell formation associated with CD36 downregulation and upregulation of ATP-binding cassette transporters A1 and G1 in human monocyte-derived macrophages. In human aortic smooth muscle cells, neopterin suppressed angiotensin II-induced migration and proliferation via c-Src/Raf-1/ERK1/2 downregulation without inducing apoptosis. Exogenous neopterin administration and endogenous neopterin attenuation with its neutralizing antibody for 4 weeks retarded and promoted, respectively, the development of aortic atherosclerotic lesions in apolipoprotein E-deficient mice. CONCLUSIONS:Our results indicate that neopterin prevents both vascular inflammation and atherosclerosis and may be induced to counteract the progression of atherosclerotic lesions. Consequently, neopterin could be of use as a novel therapeutic target for atherosclerotic cardiovascular diseases.

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Effects of niacin on atherosclerosis and vascular function.

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Effects of niacin on atherosclerosis and vascular function.

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