Lipid-lowering therapy with statins reduces microparticle shedding from endothelium, platelets and inflammatory cells

Rosa Suades; Teresa Padró; Rodrigo Alonso; Pedro Mata; Lina Badimon

doi:10.1160/TH13-03-0238

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2013; 110(02): 366-377
DOI: 10.1160/TH13-03-0238

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Lipid-lowering therapy with statins reduces microparticle shedding from endothelium, platelets and inflammatory cells

Rosa Suades

¹Cardiovascular Research Center (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain

²CIBERobn – Pathophysiology of Obesity and Nutrition, Barcelona, Spain

,

Teresa Padró

¹Cardiovascular Research Center (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain

²CIBERobn – Pathophysiology of Obesity and Nutrition, Barcelona, Spain

,

Rodrigo Alonso

³Jimenez Diaz Foundation, Madrid, Spain

,

Pedro Mata

³Jimenez Diaz Foundation, Madrid, Spain

,

Lina Badimon

¹Cardiovascular Research Center (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain

²CIBERobn – Pathophysiology of Obesity and Nutrition, Barcelona, Spain

⁴Cardiovascular Research Chair, UAB, Barcelona, Spain

› Institutsangaben

Abstract

Summary

Hyperlipidaemia is a causal factor in the ethiopathogenesis of atherosclerosis. Statins are the cornerstone drug therapy for LDL-cholesterol (LDL-c) lowering, that exert beneficial effects beyond lipid lowering. Circulating microparticles (cMPs), microvesicles released by activated cells into the bloodstream, are markers of vascular and inflammatory cell activation with tentative role in disease progression. However, the role of statins on cMPs seems controversial. We aimed at the evaluation of the effects of lipid-lowering treatment (LLT) on cMP generation in patients in primary prevention of atherosclerosis. A case-control study was conducted in hypercholesterolaemic patients receiving LLT with statins and normocholesterolaemic controls (LLT⁺ and LLT⁻, respectively, n=37/group), matched by age, gender and LDL-c levels. cMPs were characterised by flow cytometry using annexin-V and cellspecific antibodies. In LLT⁺-patients overall numbers of cMPs (p<0.005) were lower than in controls. Levels of cMPs carrying parental cell markers from vascular and circulating cell origin (platelet, endothelial cell, pan-leukocyte and specific-leukocyte subsets) were significantly lower in blood of LLT⁺ compared to LLT⁻-patients. Moreover, MPs from LLT⁺-patients had reduced markers of activated platelets (α_IIbβ₃-integrin), activated inflammatory cells (α_M-integrin) and tissue factor. The effect of LLT on cMP shedding was found to be accumulative in years. cMP shedding associated to cardiovascular risk in LLT⁺-patients. In summary, at similar plasma cholesterol levels patients on statin treatment had a significant lower number of cMPs carrying markers of activated cells. These findings indicate that statins protect against vascular cell activation.

Keywords

Atherosclerosis - circulating microparticles - inflammation - statins - thrombosis

Volltext

Referenzen

References
1 Baigent C, Keech A, Kearney PM. et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267-1278.
2 Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. Br Med J 2003; 326: 1423.
3 Landmesser U, Bahlmann F, Mueller M. et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 2005; 111: 2356-2363.
4 Sposito AC, Chapman MJ. Statin therapy in acute coronary syndromes: mechanistic insight into clinical benefit. Arterioscler Thromb Vasc Biol 2002; 22: 1524-1534.
5 Undas A, Brummel-Ziedins KE, Mann KG. Statins and blood coagulation. Arterioscler Thromb Vasc Biol 2005; 25: 287-294.
6 Kozai T, Eto M, Yang Z. et al. Statins prevent pulsatile stretch-induced proliferation of human saphenous vein smooth muscle cells via inhibition of Rho/Rhokinase pathway. Cardiovasc Res 2005; 68: 475-482.
7 Takai Y, Sasaki T, Matozaki T. Small GTP-binding proteins. Physiol Rev 2001; 81: 153-208.
8 Montoro-Garcia S, Shantsila E, Marin F. et al. Circulating microparticles: new insights into the biochemical basis of microparticle release and activity. Basic Res Cardiol 2011; 106: 911-923.
9 Jy W, Horstman LL, Jimenez JJ. et al. Measuring circulating cell-derived microparticles. J Thromb Haemost 2004; 02: 1842-1851.
10 Boulanger CM, Dignat-George F. Microparticles: an introduction. Arterioscler Thromb Vasc Biol 2011; 31: 2-3.
11 Boulanger CM. Microparticles, vascular function and hypertension. Curr Opin Nephrol Hypertens 2010; 19: 177-180.
12 Suades R, Padro T, Vilahur G. et al. Circulating and platelet-derived microparticles in human blood enhance thrombosis on atherosclerotic plaques. Thromb Haemost 2012; 108: 1208-1219.
13 Berckmans RJ, Nieuwland R, Boing AN. et al. Cell-derived microparticles circulate in healthy humans and support low grade thrombin generation. Thromb Haemost 2001; 85: 639-646.
14 Amabile N, Guerin AP, Tedgui A. et al. Predictive value of circulating endothelial microparticles for cardiovascular mortality in end-stage renal failure: a pilot study. Nephrol Dial Transplant 2011; 27: 1873-1880.
15 Namba M, Tanaka A, Shimada K. et al. Circulating platelet-derived microparticles are associated with atherothrombotic events: a marker for vulnerable blood. Arterioscler Thromb Vasc Biol 2007; 27: 255-256.
16 Sinning JM, Losch J, Walenta K. et al. Circulating CD31+/Annexin V+ microparticles correlate with cardiovascular outcomes. Eur Heart J 2010; 32: 2034-2041.
17 Diamant M, Nieuwland R, Pablo RF. et al. Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus. Circulation 2002; 106: 2442-2447.
18 Koga H, Sugiyama S, Kugiyama K. et al. Elevated levels of VE-cadherin-positive endothelial microparticles in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 2005; 45: 1622-1630.
19 Hoyer FF, Giesen MK, Nunes CFranca. et al. Monocytic microparticles promote atherogenesis by modulating inflammatory cells in mice. J Cell Mol Med 2012; 16: 2777-2788.
20 Shantsila E, Kamphuisen PW, Lip GY. Circulating microparticles in cardiovascular disease: implications for atherogenesis and atherothrombosis. J Thromb Haemost 2010; 08: 2358-2368.
21 Montoro-Garcia S, Orenes-Pinero E, Marin F. et al. Pharmacological modulation of microparticle release: new strategies for the management of atherothrombotic vascular disorders. Curr Pharm Des 2012; 18: 840-849.
22 Diamant M, Tushuizen ME, Abid-Hussein MN. et al. Simvastatin-induced endothelial cell detachment and microparticle release are prenylation dependent. Thromb Haemost 2008; 100: 489-497.
23 Nomura S. Statin and endothelial cell-derived microparticles. Thromb Haemost 2008; 100: 377-378.
24 Tramontano AF, O’Leary J, Black AD. et al. Statin decreases endothelial microparticle release from human coronary artery endothelial cells: implication for the Rho-kinase pathway. Biochem Biophys Res Commun 2004; 320: 34-38.
25 Mobarrez F, Egberg N, Antovic J. et al. Release of endothelial microparticles in vivo during atorvastatin treatment; a randomized double-blind placebo-controlled study. Thromb Res 2012; 129: 95-97.
26 Montoro-Garcia S, Lip GY, Shantsila E. Atorvastatin and its collateral effects on microparticles. Thromb Haemost 2011; 106: 185-186.
27 Mobarrez F, He S, Broijersen A. et al. Atorvastatin reduces thrombin generation and expression of tissue factor, P-selectin and GPIIIa on platelet-derived microparticles in patients with peripheral arterial occlusive disease. Thromb Haemost 2011; 106: 344-352.
28 Tehrani S, Mobarrez F, Antovic A. et al. Atorvastatin has antithrombotic effects in patients with type 1 diabetes and dyslipidemia. Thromb Res 2010; 126: e225-231.
29 Nomura S, Shouzu A, Omoto S. et al. Losartan and simvastatin inhibit platelet activation in hypertensive patients. J Thromb Thrombolysis 2004; 18: 177-185.
30 Nomura S, Shouzu A, Omoto S. et al. Effects of losartan and simvastatin on monocyte-derived microparticles in hypertensive patients with and without type 2 diabetes mellitus. Clin Appl Thromb Hemost 2004; 10: 133-141.
31 Sommeijer DW, Joop K, Leyte A. et al. Pravastatin reduces fibrinogen receptor gpIIIa on platelet-derived microparticles in patients with type 2 diabetes. J Thromb Haemost 2005; 03: 1168-1171.
32 Nomura S, Inami N, Shouzu A. et al. The effects of pitavastatin, eicosapentaenoic acid and combined therapy on platelet-derived microparticles and adiponectin in hyperlipidemic, diabetic patients. Platelets 2009; 20: 16-22.
33 Owens 3rd AP, Passam FH, Antoniak S. et al. Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin. J Clin Invest 2012; 122: 558-568.
34 Mata N, Alonso R, Badimon L. et al. Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART). Lipids Health Dis 2011; 10: 94.
35 Gehi AK, Ali S, Na B. et al. Self-reported medication adherence and cardiovascular events in patients with stable coronary heart disease: the heart and soul study. Arch Intern Med 2007; 167: 1798-1803.
36 Pijlman AH, Huijgen R, Verhagen SN. et al. Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands. Atherosclerosis 2010; 209: 189-194.
37 Graham I, Atar D, Borch-Johnsen K. et al. European guidelines on cardiovascular disease prevention in clinical practice: executive summary: Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (Constituted by representatives of nine societies and by invited experts). Eur Heart J 2007; 28: 2375-2414.
38 Wierzbicki AS, Humphries SE, Minhas R. Familial hypercholesterolaemia: summary of NICE guidance. Br Med J 2008; 337: a1095.
39 Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002 106. 3143-3421.
40 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502.
41 Mozas P, Castillo S, Tejedor D. et al. Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR. Hum Mutat 2004; 24: 187.
42 Nieuwland R, Berckmans RJ, McGregor S. et al. Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood 2000; 95: 930-935.
43 Rank A, Nieuwland R, Roesner S. et al. Climacteric lowers plasma levels of platelet-derived microparticles: a pilot study in pre-versus postmenopausal women. Acta Haematol 2012; 128: 53-59.
44 Biro E, Akkerman JW, Hoek FJ. et al. The phospholipid composition and cholesterol content of platelet-derived microparticles: a comparison with platelet membrane fractions. J Thromb Haemost 2005; 03: 2754-2763.
45 Lacroix R, Robert S, Poncelet P. et al. Standardization of platelet-derived microparticle enumeration by flow cytometry with calibrated beads: results of the International Society on Thrombosis and Haemostasis SSC Collaborative workshop. J Thromb Haemost 2010; 08: 2571-2574.
46 Nieuwland R, Berckmans RJ, Rotteveel-Eijkman RC. et al. Cell-derived microparticles generated in patients during cardiopulmonary bypass are highly procoagulant. Circulation 1997; 96: 3534-3541.
47 Williams JC, Mackman N. MPs or ICs?. Blood 2011; 117: 1101-1102.
48 van der Pol E, van Gemert MJ, Sturk A. et al. Single vs. swarm detection of microparticles and exosomes by flow cytometry. J Thromb Haemost 2012; 10: 919-930.
49 Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011; 473: 317-325.
50 Badimon L, Storey RF, Vilahur G. Update on lipids, inflammation and atherothrombosis. Thromb Haemost 2011; 105 (Suppl. 01) S34-42.
51 Badimon L, Vilahur G, Padro T. Lipoproteins, platelets and atherothrombosis. Rev Esp Cardiol 2009; 62: 1161-1178.
52 Nomura S, Omoto S, Yokoi T. et al. Effects of miglitol in platelet-derived microparticle, adiponectin, and selectin level in patients with type 2 diabetes mellitus. Int J Gen Med 2011; 04: 539-545.
53 Nomura S, Shouzu A, Omoto S. et al. Effects of eicosapentaenoic acid on endothelial cell-derived microparticles, angiopoietins and adiponectin in patients with type 2 diabetes. J Atheroscler Thromb 2009; 16: 83-90.
54 Martin S, Tesse A, Hugel B. et al. Shed membrane particles from T lymphocytes impair endothelial function and regulate endothelial protein expression. Circulation 2004; 109: 1653-1659.
55 Wang JG, Williams JC, Davis BK. et al. Monocytic microparticles activate endothelial cells in an IL-1beta-dependent manner. Blood 2011; 118: 2366-2374.
56 Topol EJ. Intensive statin therapy--a sea change in cardiovascular prevention. N Engl J Med 2004; 350: 1562-1564.
57 Shepherd J, Cobbe SM, Ford I. et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995; 333: 1301-1307.
58 Downs JR, Clearfield M, Weis S. et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. J Am Med Assoc 1998; 279: 1615-1622.
59 Sever PS, Dahlof B, Poulter NR. et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361: 1149-1158.
60 Ridker PM, Danielson E, Fonseca FA. et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195-2207.
61 Ray KK, Seshasai SR, Erqou S. et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch Intern Med 2010; 170: 1024-1031.
62 Marrugat J, Solanas P, D’Agostino R. et al. Coronary risk estimation in Spain using a calibrated Framingham function. Rev Esp Cardiol 2003; 56: 253-261.

Zusatzmaterial

Zusatzmaterial