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

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 cell-specific 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 (αIIbβ3-integrin), activated inflammatory cells (αM-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.

[1]  G. Vilahur,et al.  Circulating and platelet-derived microparticles in human blood enhance thrombosis on atherosclerotic plaques , 2012, Thrombosis and Haemostasis.

[2]  G. Nickenig,et al.  Monocytic microparticles promote atherogenesis by modulating inflammatory cells in mice , 2012, Journal of cellular and molecular medicine.

[3]  Shah Ebrahim,et al.  European Guidelines on Cardiovascular Disease Prevention in Clinical Practice (Version 2012) , 2012, International Journal of Behavioral Medicine.

[4]  R. Nieuwland,et al.  Climacteric Lowers Plasma Levels of Platelet-Derived Microparticles: A Pilot Study in Pre- versus Postmenopausal Women , 2012, Acta Haematologica.

[5]  M. V. van Gemert,et al.  Single vs. swarm detection of microparticles and exosomes by flow cytometry , 2012, Journal of thrombosis and haemostasis : JTH.

[6]  G. London,et al.  Predictive value of circulating endothelial microparticles for cardiovascular mortality in end-stage renal failure: a pilot study. , 2012, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[7]  D. Johns,et al.  Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin. , 2012, The Journal of clinical investigation.

[8]  G. Lip,et al.  Pharmacological modulation of microparticle release: new strategies for the management of atherothrombotic vascular disorders. , 2012, Current pharmaceutical design.

[9]  N. Egberg,et al.  Release of endothelial microparticles in vivo during atorvastatin treatment; a randomized double-blind placebo-controlled study. , 2012, Thrombosis research.

[10]  Ken Jacobson,et al.  Monocytic microparticles activate endothelial cells in an IL-1β-dependent manner. , 2011, Blood.

[11]  S. Nomura,et al.  Effects of miglitol in platelet-derived microparticle, adiponectin, and selectin level in patients with type 2 diabetes mellitus , 2011, International journal of general medicine.

[12]  G. Lip,et al.  Circulating microparticles: new insights into the biochemical basis of microparticle release and activity , 2011, Basic Research in Cardiology.

[13]  E. Guallar,et al.  Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART) , 2011, Lipids in Health and Disease.

[14]  H. Wallen,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 , 2011, Thrombosis and Haemostasis.

[15]  G. Lip,et al.  Atorvastatin and its collateral effects on microparticles , 2011, Thrombosis and Haemostasis.

[16]  P. Libby,et al.  Progress and challenges in translating the biology of atherosclerosis , 2011, Nature.

[17]  G. Vilahur,et al.  Update on lipids, inflammation and atherothrombosis , 2011, Thrombosis and Haemostasis.

[18]  G. Nickenig,et al.  Circulating CD 31 1 / Annexin V 1 microparticles correlate with cardiovascular outcomes , 2011 .

[19]  N. Mackman,et al.  MPs or ICs? , 2011, Blood.

[20]  Microparticles: An Introduction , 2011, Arteriosclerosis, thrombosis, and vascular biology.

[21]  R Lacroix,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 , 2010, Journal of thrombosis and haemostasis : JTH.

[22]  G. Lip,et al.  Circulating microparticles in cardiovascular disease: implications for atherogenesis and atherothrombosis , 2010, Journal of thrombosis and haemostasis : JTH.

[23]  P. Henriksson,et al.  Atorvastatin has antithrombotic effects in patients with type 1 diabetes and dyslipidemia. , 2010, Thrombosis research.

[24]  J Wouter Jukema,et al.  Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. , 2010, Archives of internal medicine.

[25]  C. Boulanger.  Microparticles, vascular function and hypertension , 2010, Current opinion in nephrology and hypertension.

[26]  J. Kastelein,et al.  Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands. , 2010, Atherosclerosis.

[27]  L. Badimón,et al.  Lipoproteínas, plaquetas y aterotrombosis , 2009 .

[28]  G. Vilahur,et al.  Lipoproteins, platelets and atherothrombosis. , 2009, Revista espanola de cardiologia.

[29]  S. Nomura,et al.  Effects of eicosapentaenoic acid on endothelial cell-derived microparticles, angiopoietins and adiponectin in patients with type 2 diabetes. , 2009, Journal of atherosclerosis and thrombosis.

[30]  T. Iwasaka,et al.  The effects of pitavastatin, eicosapentaenoic acid and combined therapy on platelet-derived microparticles and adiponectin in hyperlipidemic, diabetic patients , 2009, Platelets.

[31]  G. Moneta,et al.  Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein , 2009 .

[32]  S. Humphries,et al.  Familial hypercholesterolaemia: summary of NICE guidance , 2008, BMJ : British Medical Journal.

[33]  S. Nomura.  Statin and endothelial cell-derived microparticles , 2008, Thrombosis and Haemostasis.

[34]  R. Nieuwland,et al.  Simvastatin-induced endothelial cell detachment and microparticle release are prenylation dependent , 2008, Thrombosis and Haemostasis.

[35]  Shah Ebrahim,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 invit , 2007, European heart journal.

[36]  Mary A Whooley,et al.  Self-reported medication adherence and cardiovascular events in patients with stable coronary heart disease: the heart and soul study. , 2007, Archives of internal medicine.

[37]  Shah Ebrahim,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 invit , 2007, European heart journal.

[38]  K. Shimada,et al.  Circulating platelet-derived microparticles are associated with atherothrombotic events: a marker for vulnerable blood. , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[39]  R. Nieuwland,et al.  The phospholipid composition and cholesterol content of platelet‐derived microparticles: a comparison with platelet membrane fractions , 2005, Journal of thrombosis and haemostasis : JTH.

[40]  Hiroaki Shimokawa,et al.  Statins prevent pulsatile stretch-induced proliferation of human saphenous vein smooth muscle cells via inhibition of Rho/Rho-kinase pathway. , 2005, Cardiovascular research.

[41]  R. Collins,et al.  Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins , 2005, The Lancet.

[42]  P. Reitsma,et al.  Pravastatin reduces fibrinogen receptor gpIIIa on platelet‐derived microparticles in patients with type 2 diabetes , 2005, Journal of thrombosis and haemostasis : JTH.

[43]  Tomohiro Sakamoto,et al.  Elevated levels of VE-cadherin-positive endothelial microparticles in patients with type 2 diabetes mellitus and coronary artery disease. , 2005, Journal of the American College of Cardiology.

[44]  W. März,et al.  Simvastatin Versus Ezetimibe: Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans , 2005, Circulation.

[45]  T. Iwasaka,et al.  Losartan and Simvastatin Inhibit Platelet Activation in Hypertensive Patients , 2004, Journal of Thrombosis and Thrombolysis.

[46]  K. Mann,et al.  Statins and Blood Coagulation , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[47]  R. Nieuwland,et al.  Measuring circulating cell‐derived microparticles , 2004, Journal of thrombosis and haemostasis : JTH.

[48]  M. Pocovi,et al.  Molecular characterization of familial hypercholesterolemia in Spain: Identification of 39 novel and 77 recurrent mutations in LDLR , 2004, Human mutation.

[49]  A. D. Black,et al.  Statin decreases endothelial microparticle release from human coronary artery endothelial cells: implication for the Rho-kinase pathway. , 2004, Biochemical and biophysical research communications.

[50]  E. Topol.  Intensive statin therapy--a sea change in cardiovascular prevention. , 2004, The New England journal of medicine.

[51]  Toshiji Iwasaka,et al.  Effects of Losartan and Simvastatin on Monocyte-Derived Microparticles in Hypertensive Patients With and Without Type 2 Diabetes Mellitus , 2004, Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis.

[52]  R. Andriantsitohaina,et al.  Shed Membrane Particles From T Lymphocytes Impair Endothelial Function and Regulate Endothelial Protein Expression , 2004, Circulation.

[53]  N. Poulter,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☆ , 2003 .

[54]  N J Wald,et al.  Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis , 2003, BMJ : British Medical Journal.

[55]  J. Marrugat,et al.  Estimación del riesgo coronario en España mediante la ecuación de Framingham calibrada , 2003 .

[56]  R. D'Agostino,et al.  [Coronary risk estimation in Spain using a calibrated Framingham function]. , 2003, Revista espanola de cardiologia.

[57]  J. Mckenney,et al.  National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) , 2002 .

[58]  R. Nieuwland,et al.  Elevated Numbers of Tissue-Factor Exposing Microparticles Correlate With Components of the Metabolic Syndrome in Uncomplicated Type 2 Diabetes Mellitus , 2002, Circulation.

[59]  A. Sposito,et al.  Statin Therapy in Acute Coronary Syndromes: Mechanistic Insight Into Clinical Benefit , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[60]  S. Grundy,et al.  National Cholesterol Education Program 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 , 2022 .

[61]  C. Hack,et al.  Cell-derived Microparticles Circulate in Healthy Humans and Support Low Grade Thrombin Generation , 2001, Thrombosis and Haemostasis.

[62]  R. Westendorp,et al.  Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. , 2000, Blood.

[63]  A. Gotto,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. , 1998, JAMA.

[64]  K. Maquelin,et al.  Cell-derived microparticles generated in patients during cardiopulmonary bypass are highly procoagulant. , 1997, Circulation.

[65]  P. Macfarlane,et al.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia , 1995 .

[66]  P. Macfarlane,et al.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. , 1995, The New England journal of medicine.

[67]  K. Kaibuchi,et al.  Small GTP-binding proteins. , 1992, International review of cytology.

[68]  R. Levy,et al.  Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. , 1972, Clinical chemistry.