The in vitro effects of niacin on platelet biomarkers in human volunteers

Victor Serebruany; Alex Malinin; Daniel Aradi; Wiktor Kuliczkowski; Nicholas B. Norgard; William E. Boden

doi:10.1160/TH10-01-0015

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 104(02): 311-317
DOI: 10.1160/TH10-01-0015

Platelets and Blood Cells

Schattauer GmbH

The in vitro effects of niacin on platelet biomarkers in human volunteers

Victor Serebruany

¹HeartDrug™ Research Laboratories, Johns Hopkins University, Baltimore, Maryland, USA

,

Alex Malinin

¹HeartDrug™ Research Laboratories, Johns Hopkins University, Baltimore, Maryland, USA

,

Daniel Aradi

²University of Pecs, Pecs, Hungary

,

Wiktor Kuliczkowski

³University of Wroclaw, Wroclaw, Poland

,

Nicholas B. Norgard

⁴University of Buffalo, Buffalo, New York, USA

,

William E. Boden

⁴University of Buffalo, Buffalo, New York, USA

› Author Affiliations

Abstract

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Summary

Niacin is a natural pyridine derivative, proven to favorably modulate the blood lipid profile by increasing levels of high-density lipoprotein (HDL) cholesterol, and by reducing total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and Lp (a) lipoprotein concentrations. Considering that platelet activity is important in predicting vascular outcomes, and that HDL heavily constitutes platelet cellular membranes, we sought to evaluate the effect of niacin on human platelet activity indices. The blood obtained from 30 aspirin-naïve volunteers was preincubated with escalating concentrations of niacin in vitro. Platelet tests included whole blood and plasma aggregometry, rapid cartridgebased analyser, expression of major surface receptors by flow cytometry, and plasma prostaglandins by ELISA. Preincubation of blood with niacin at 0.3, 1.0 and 3.0 mM resulted in significant inhibition of maximal adenosine diphosphate (ADP)- (p=0.03), and collagen-induced platelet aggregation (p=0.01), and reduced activity by VerifyNow™ (p=0.007) bedside analyser. Surface platelet PAR-1 (MoAb WEDE-15; p=0.04), and vitronectin (CD51/CD61; p=0.02) receptors were up-regulated. Niacin was associated with a two- to three-fold increase of thromboxane B2, prostaglandins D2, and E2. Formation of platelet-monocyte microparticles (CD14+CD151), and expression of PECAM-1 (CD31), thrombospondin (CD36), GP IIb/IIIa (CD41a) antigen, and activity with MoAb PAC-1, GPIb (CD42b), P-selectin (CD62p), LAMP-3 (CD63), LAMP-1 (CD107a), CD40-ligand (CD154), GP37 (CD165), were not affected by niacin, suggesting no effect on prostacyclin release. In conclusion, niacin in vitro affects platelet activity by mildly inhibiting aggregation, and stimulating significant prostaglandin release, with mostly intact major platelet receptor expression. The effect of niacin is unique, differs from other known antiplatelet agents, and suggests potential opportunities for therapeutic combination, particularly in patients with low levels of HDL-C. These preliminary data, while intriguing, require confirmation in subjects receiving orally dosed extended-release niacin in order to determine whether these findings are clinically relevant.

Keywords

Niacin - lipids - platelets - in vitro

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References

References
1 Libby P. Changing concepts of atherogenesis. J Intern Med 2000; 247: 349-358.
2 Steinberg D, Parthasarathy S, Carew TE. et al. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989; 320: 915-924.
3 Relou IA, Hackeng CM, Akkerman JW. et al. Low-density lipoprotein and its effect on human blood platelets. Cell Mol Life Sci 2003; 60: 961-971.
4 García-Guerra R, Mateo CR, García-Muñ MS. et al. Distinct cholesterol and phospholipid incorporation at the platelet plasma membrane of hyperlipidemic subjects: structural order and function. Platelets 1998; 09: 365-373.
5 Ravindran R, Krishnan LK. et al. Increased platelet cholesterol and decreased percentage volume of platelets as a secondary risk factor for coronary artery disease. Pathophysiol Haemost. Thromb 2007; 36: 45-51.
6 Digby JE, Lee JM, Choudhury RP. Nicotinic acid and the prevention of coronary artery disease. Curr Opin Lipidol 2009; 20: 321-326.
7 Vosper H. Niacin: a re-emerging pharmaceutical for the treatment of dyslipidaemia. Br J Pharmacol 2009; 158: 429-441.
8 Kamanna VS, Kashyap ML. Mechanism of action of niacin. Am J Cardiol 2008; 101: 20B-26B.
9 Shobha H, Ganji S Tavintharan. et al. Niacin noncompetitively inhibits DGAT2 but not DGAT1 activity in HepG2 cells. J Lipid Res 2004; 45: 1835-1845.
10 Collet JP, Montalescot G. Platelet function testing and implications for clinical practice. J Cardiovasc Pharmacol Ther 2009; 14: 157-169.
11 McGlasson DL, Fritsma GA. Whole blood platelet aggregometry and platelet function testing. Semin Thromb Hemost 2009; 35: 168-180.
12 Lordkipanidzé M, Diodati JG, Schampaert E. et al. Prevalence of unresponsiveness to aspirin and/or clopidogrel in patients with stable coronary heart disease. Am J Cardiol 2009; 104: 1189-1193.
13 Serebruany VL, Kogushi M, Dastros-Pitei D. et al. The invitro effects of E5555, a protease-activated receptor (PAR)-1 antagonist, on platelet biomarkers in healthy volunteers and patients with coronary artery disease. Thromb Haemost 2009; 102: 111-119.
14 Zeidan AM, Kouides PA, Tara MA. et al. Platelet function testing: state of the art. Expert Rev Cardiovasc Ther 2007; 05: 955-967.
15 Serebruany VL, Gurbel PA. The relations of major platelet receptor expression during myocardial infarction. Monitoring efficacy of GPIIb/IIIa inhibitors by measuring P – selectin?. Thromb Haemost 1999; 81: 314-316.
16 Serebruany VL, Gurbel PA, O’Connor CM. Platelet Inhibition by Sertraline and N-Desmethylsertraline : A Possible Missing Link Between Depression, Coronary Events, and Mortality Benefits of Selective Serotonin Reuptake Inhibitors. Pharm Res 2001; 43: 453-462.
17 Serebruany VL, Malinin I A, Scott R. The in vitro effects of a novel vascular protectant, AGI-1067, on platelet aggregation and major receptor expression in subjects with multiple risk factors for vascular disease. J Cardiovasc Pharm Ther 2006; 11: 1-6.
18 Serebruany V, Malinin A, Goodin T. et al. The in vitro effects of Xancor, synthetic astaxanthine derivative, on hemostatic biomarkers in aspirin naïve, and aspirin treated subjects with multiple risk factors for vascular disease. Am J Ther 2010; in press.
19 Hallén J, Atar D, Serebruany V. Effects of FX06 In Vitro on Platelet, Coagulation, and Fibrinolytic Biomarkers in Volunteers and Patients With Documented Cor-onary Artery Disease. Am J Ther 2010; in press.
20 Serebruany VL, Malinin I A, Lowry DR. et al. Platelet Inhibition by Valsartan and Valeryl 4-hydroxy Valsartan: A Possible Missing Link to Explain Benefits of Angiotensin II Receptor Blockers in Patients After Acute Vascular Events. J Cardiovasc Pharm 2004; 43: 677-684.
21 Relou IA, Hackeng CM, Akkerman JW. et al. Low-density lipoprotein and its effect on human blood platelets. Cell Mol Life Sci 2003; 60: 961-971.
22 Mehta JL, Chen LY. Reversal by high-density lipoprotein of the effect of oxidized low-density lipoprotein on nitric oxide synthase protein expression in human platelets. J Lab Clin Med 1996; 127: 287-295.
23 Riddell DR, Graham A, Owen JS. Apolipoprotein E inhibits platelet aggregation through the L-arginine: nitric oxide pathway. Implications for vascular disease. J Biol Chem 1997; 272: 89-95.
24 Riddell DR, Owen JS. Inhibition of ADP-induced platelet aggregation by apoE is not mediated by membrane cholesterol depletion. Thromb Res 1996; 81: 597-606.
25 Desai K, Bruckdorfer KR, Hutton RA. et al. Binding of apoE-rich high density lipoprotein particles by saturable sites on human blood platelets inhibits agonist-induced platelet aggregation. J Lipid Res 1989; 30: 831-840.
26 Curtiss LK, Plow EF. Interaction of plasma lipoproteins with human platelets. Blood 1984; 64: 365-374.
27 Nofer JR, Tepel M, Kehrel B. et al. High density lipoproteins enhance the Na+/H+ antiport in human platelets. Thromb Haemost 1996; 75: 635-641.
28 Nofer JR, Walter M, Kehrel B. et al. HDL3 activates phospholipase D in normal but not in glycoprotein IIb/IIIa-deficient platelets. Biochem Biophys Res Commun 1995; 207: 148-154.
29 Graham D, Simpson HD, Dominiczak AF. et al. In vivo and in vitro studies of the role of HDL in platelet activation in normotensive and hypertensive subjects. J Hum Hypertens 1995; 09: 753-758.
30 Ardlie NG, Selley ML, Simons LA. Platelet activation by oxidatively modified low density lipoproteins. Atherosclerosis 1989; 76: 117-124.
31 Goldberg A, Alagona Jr P, Capuzzi DM. et al. Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia. Am J Cardiol 2000; 85: 1100-1105.
32 Nagakawa Y, Orimo H, Harasawa M. The anti-platelet effect of niceritrol in patients with arteriosclerosis and the relationship of the lipid-lowering effect to the anti-platelet effect. Thromb Res 1985; 40: 543-553.
33 Vincent JE, Zijlstra FJ. Nicotinic acid inhibits thromboxane synthesis in platelets. Prostaglandins 1978; 15: 629-636.
34 Kamanna VS, Ganji SH, Kashyap ML. The mechanism and mitigation of niacin-induced flushing. Int J Clin Pract 2009; 63: 1369-1377.
35 Papaliodis D, Boucher W, Kempuraj D. et al. Niacin-induced „flush“ involves release of prostaglandin D2 from mast cells and serotonin from platelets: evidence from human cells in vitro and an animal model. J Pharmacol Exp Ther 2008; 327: 665-672.
36 Saareks V, Ylitalo P, Mucha I. et al. Opposite effects of nicotinic acid and pyridoxine on systemic prostacyclin, thromboxane and leukotriene production in man. Pharmacol Toxicol 2002; 90: 338-342.
37 Pattison A, Eason CT, Bonner FW. Nicotinic acid enhances the production of 6-ketoprostaglandin F1 alpha in human whole blood in vitro. Res Commun Chem Pathol Pharmacol 1987; 55: 423-426.