Subscribe to RSS
DOI: 10.1055/s-0037-1613086
Increased Superoxide Anion Production by Platelets in Hypercholesterolemic Patients
Publication History
Received
14 November 2001
Accepted after revision
14 January 2002
Publication Date:
11 December 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200205/lookinside/thumbnails/10-1055-s-0037-1613086-1.jpg)
Summary
Objectives
The purpose of this study was to investigate the relationship between hypercholesterolemia and superoxide anion production.
Background
Experimental studies demonstrated that hypercholesterolemia is associated with enhanced cellular superoxide anion (O2 −) production. Aim of the study was to assess whether the same phenomenon occurs in humans.
Methods
Lipid profile and platelet O2 − production were measured in 28 patients with hypercholesterolemia, compared with 25 age- and sexmatched healthy subjects, and in 21 out of the 28 patients after 8-week treatment with 10 mg/day atorvastatin (a HMGCoA reductase inhibitor). In order to assess the mechanism by which LDL cholesterol interferes with platelet production of O2 −, human platelets were incubated with LDL cholesterol in the presence of either an inhibitor of the phospholipaseA2 enzyme, AACOCF3, or an inhibitor of NADH/NADPH oxidases, DPI.
Results
O2 − platelet generation was significantly higher (p <0.001) and significantly related to LDL cholesterol (p < 0.001 ) in patients as compared to controls. 8-week treatment with 10 mg/day atorvastatin significantly reduced both LDL cholesterol and O2 − platelet production. This effect was partially related to the cholesterol-lowering, in that three days of treatment with atorvastatin significantly decreased platelet O2 − production, while no significant change in LDL-cholesterol levels was observed. Platelets incubated with LDL cholesterol showed O2 − release by atorvastatin is partially related to cholesterol lowering effect, suggesting that other mechanisms could be responsible for the antioxidant activity of the drug.
Condensed Abstract
Platelets O2 − production is enhanced in patients with hypercholesterolemia and significantly correlated with LDL cholesterol. Treatment of hypercholesterolemic patients with atorvastatin inhibited platelet O2 − production through a mechanism which is partially dependent on its cholesterol lowering effect, indicating a non-lipid lowering antioxidant effect. In vitro incubation of platelets with LDL cholesterol enhanced O2 − production which was inhibited by inhibitors of phospholipase A2 and NADH/NADPH enzymes, suggesting that these pathways contribute to LDL-induced platelet O2– production.
-
References
- 1 Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4,444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383-89.
- 2 Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effects of pravastatin on coronary events after myocardial infarction in patients with average cholesterol level. N Engl J Med 1996; 335: 1001-9.
- 3 Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. The West of Scotland coronary prevention group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301-7.
- 4 Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modification of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989; 320: 915-24.
- 5 Witztum JL. The oxidation hypothesis of atherosclerosis. Lancet 1994; 334: 793-5.
- 6 Iuliano L, Mauriello A, Sbarigia E, Spagnoli LG, Violi F. Radiolabeled native low-density lipoprotein injected into patients with carotid stenosis accumulates in macrophages of atherosclerotic plaque. Effect of vitamin E supplementation. Circulation 2000; 101: 1249-54.
- 7 Praticò D, Tangirala RK, Rader DJ, Rokach J, FitzGerald GA. Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in Apo E-deficient mice. Nat Med 1998; 04: 1189-92.
- 8 Davì G, Alessandrini P, Mezzetti A, Minotti G, Bucciarelli T, Costantini F, Cipollone F, Bon GB, Ciabattoni G, Patrono C. In vivo formation of 8-Epiprostaglandin F2 is increased in hypercholesterolemia. Arterioscler Thromb Vasc Biol 1997; 17: 3230-5.
- 9 Reilly MP, Praticò D, Delanty N, DiMinno G, Tremoli E, Rader D, Kapoor S, Rokach J, Lawson J, FitzGerald GA. Increased formation of distinct F2 isoprostanes in hypercholesterolemia. Circulation 1998; 98: 2822-28.
- 10 Vergnani L, Hatrik S, Ricci F, Passaro A, Manzoli N, Zuliani G, Brovkovych V, Fellin R, Malinski T. Effect of native and oxidized low-density lipoprotein on endothelial nitric oxide and superoxide production: key role of L-Arginine availability. Circulation 2000; 101: 1261-6.
- 11 Ohara Y, Peterson TE, Sayegh HS, Subramanian RR, Wilcox JN, Harrison DG. Dietary correction of Hypercholesterolemia in the rabbit normalizes endothelial superoxide anion production. Circulation 1995; 92: 898-903.
- 12 Violi F, Marino R, Milite MT, Loffredo L. Nitric oxide and its role in lipid peroxidation. Diabetes Metab Res Rev 1999; 15: 283-8.
- 13 Leo R, Praticò D, Iuliano L, Pulcinelli FM, Ghiselli A, Pignatelli P, Colavita AR, FitzGerald GA, Violi F. Platelet activation by superoxide anion and hydroxyl radicals intrinsically generated by platelets that undergone anoxia and then reoxygenated. Circulation 1997; 95: 885-91.
- 14 Freedman JE, Keaney JF. Nitric oxide and superoxide detection in human platelets. Methods Enzymol 1999; 301: 61-70.
- 15 Vasquez-Vivar J, Hogg N, Pritchard Jr KA, Martasek P, Kalyanaraman B. Superoxide anion formation from lucigenin: an electron spin resonance spin-traping study. FEBS letters 1997; 403: 127-30.
- 16 Liochev SI, Fridovich I. Lucigenin (Bis-N-methylacridinium) as a mediator of superoxide anion production. Archiv Biochem Bioph 1997; 337 (01) 115-20.
- 17 Hackeng CM, Huigsloot M, Pladet MW, Nieuwenhuis HK, van Rijn HJ, Akkerman JW. Low-density lipoprotein enhances platelet secretion via integrin-alphaIIbeta3-mediated signaling. Arterioscler Thromb Vasc Biol 1999; 19: 239-47 18.
- 18 Wagner AH, Kohler T, Ruckschloss U, Just I, Hecker M. Improvement of nitric oxide-dependent vasodilatation by HMG-Coa reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol 2000; 20: 61-9.
- 19 Hackeng CM, Relou IA, Pladet MW, Gorter G, van Rijn HJ, Akkerman JW. Early platelet activation by low density lipoprotein via p38map kinase. Thromb Haemost 1999; 82: 1749-56.
- 20 Caccese D, Praticò D, Ghiselli A, Natoli S, Pignatelli P, Sanguigni V, Iuliano L, Violi F. Superoxide anion and hydroxyl radical release by colla-gen-induced platelet aggregation – Role of arachidonic acid metabolism. Thromb Haemost 2000; 83: 485-90.
- 21 Cross AR, Jones OT. The effect of the inhibitor diphenylene iodinium on the superoxide-generating system of neutrophilis. Biochem J 1986; 237: 111-6.
- 22 Sekaka A, Ida E, Tuminga M, Onoue K. Arachidonic acid acts as an intracellular activator of NADPH-oxidase in Fe gamma receptor-mediated superoxide anion generation in macrophages. J Immunology 1987; 138: 4353-9.