Update on lipids, inflammation and atherothrombosis

Lina Badimon; Robert F. Storey; Gemma Vilahur

doi:10.1160/THS10-11-0717

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2011; 105(S 06): S34-S42
DOI: 10.1160/THS10-11-0717

Thrombosis and Haemostasis Supplement

Schattauer GmbH

Update on lipids, inflammation and atherothrombosis

Authors

Lina Badimon

¹Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain

²CIBEROBN-Pathophysiology of Obesity and Nutrition – Barcelona, Spain

³Cardiovascular Research Chair, UAB, Barcelona, Spain
Robert F. Storey

⁴Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
Gemma Vilahur

¹Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain

²CIBEROBN-Pathophysiology of Obesity and Nutrition – Barcelona, Spain

Abstract

Summary

Atherosclerosis is an inflammatory disease that involves the arterial wall and is characterised by the progressive accumulation of lipids in the vessel wall. The first step is the internalisation of lipids (LDL) in the intima with endothelial activation which enhances the permeability of the endothelial layer and the expression of cytokines/chemokines and adhesion molecules. These events increase LDL particles accumulation in the extracellular matrix where they aggregate/fuse, are retained by proteoglycans and become targets for oxidative and enzymatic modifications. In turn, retained pro-atherogenic LDLs enhance selective leukocyte recruitment and attachment to the endothelial layer inducing their transmigration across the endothelium into the intima. While smooth muscle cell numbers decline with the severity of plaque progression, monocytes differentiate into macrophages, a process associated with the upregulation of pattern recognition receptors including scavenger receptors and Toll-like receptors leading to foam cell formation. Foamcells release growth factors, cytokines, metalloproteinases and reactive oxygen species all of which perpetuate and amplify the vascular remodelling process. In addition, macrophages release tissue factor that, upon plaque rupture, contributes to thrombus formation. Smooth muscle cells exposed in eroded lesions are also able to internalise LDL through LRP-1 receptors acquiring a pro-thrombotic phenotype and releasing tissue factor. Platelets recognise ligands in the ruptured or eroded atherosclerotic plaque, initiate platelet activation and aggregation leading to thrombosis and to the clinical manifestation of the atherothrombotic disease. Additionally, platelets contribute to the local inflammatory response and may also participate in progenitor cell recruitment.

Keywords

Atherosclerosis - thrombosis - inflammation

Full Text

References

References
1 Loscalzo J. Nitric oxide insufficiency, platelet activation, and arterial thrombosis. Circ Res 2001; 88: 756-762.
2 Vidal F, Colome C, Martinez-Gonzalez J. et al. Atherogenic concentrations of native low-density lipoproteins down-regulate nitric-oxide-synthase mRNA and protein levels in endothelial cells. Eur J Biochem 1998; 252: 378-384.
3 Liao JK, Shin WS, Lee WY. et al. Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem 1995; 270: 319-324.
4 Blair A, Shaul PW, Yuhanna IS. et al. Oxidized low density lipoprotein displaces endothelial nitric-oxide synthase (eNOS) from plasmalemmal caveolae and impairs eNOS activation. J Biol Chem 1999; 274: 32512-32519.
5 Badimon L, Martinez-Gonzalez J, Llorente-Cortes V. et al. Cell biology and lipoproteins in atherosclerosis. Curr Mol Med 2006; 6: 439-456.
6 Badimon L, Vilahur G, Padro T. Lipoproteins, platelets and atherothrombosis. Rev Esp Cardiol 2009; 62: 1161-1178.
7 Camejo G, Hurt-Camejo E, Wiklund O. et al. Association of apo B lipoproteins with arterial proteoglycans: pathological significance and molecular basis. Atherosclerosis 1998; 139: 205-222.
8 Csiszar A, Wang M, Lakatta EG. et al. Inflammation and endothelial dysfunction during aging: role of NF-kappaB. J Appl Physiol 2008; 105: 1333-1341.
9 Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868-874.
10 Simionescu M. Implications of early structural-functional changes in the endothelium for vascular disease. Arterioscler Thromb Vasc Biol 2007; 27: 266-274.
11 Weber C, Fraemohs L, Dejana E. The role of junctional adhesion molecules in vascular inflammation. Nat Rev Immunol 2007; 7: 467-477.
12 Swirski FK, Libby P, Aikawa E. et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 2007; 117: 195-205.
13 Passlick B, Flieger D, Ziegler-Heitbrock HW. Identification and characterization of a novel monocyte subpopulation in human peripheral blood. Blood 1989; 74: 2527-2534.
14 Hristov M, Leyendecker T, Schuhmann C. et al. Circulating monocyte subsets and cardiovascular risk factors in coronary artery disease. Thromb Haemost 2010; 104: 412-414.
15 Rogacev KS, Seiler S, Zawada AM. et al. CD14++CD16+ monocytes and cardiovascular outcome in patients with chronic kidney disease. Eur Heart J 2011; 32: 84-92.
16 Swirski FK, Weissleder R, Pittet MJ. Heterogeneous in vivo behavior of monocyte subsets in atherosclerosis. Arterioscler Thromb Vasc Biol 2009; 29: 1424-1432.
17 Sunderkotter C, Nikolic T, Dillon MJ. et al. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J Immunol 2004; 172: 4410-4417.
18 Auffray C, Fogg D, Garfa M. et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 2007; 317: 666-670.
19 Galkina E, Ley K. Immune and inflammatory mechanisms of atherosclerosis. Annu Rev Immunol 2009; 27: 165-197.
20 Lindstedt KA, Kovanen PT. Mast cells in vulnerable coronary plaques: potential mechanisms linking mast cell activation to plaque erosion and rupture. Curr Opin Lipidol 2004; 15: 567-573.
21 Collot-Teixeira S, Martin J, McDermott-Roe C. et al. CD36 and macrophages in atherosclerosis. Cardiovasc Res 2007; 75: 468-477.
22 Llorente-Cortes V, Royo T, Otero-Vinas M. et al. Sterol regulatory element binding proteins downregulate LDL receptor-related protein (LRP1) expression and LRP1-mediated aggregated LDL uptake by human macrophages. Cardiovasc Res 2007; 74: 526-536.
23 Suzuki H, Kurihara Y, Takeya M. et al. The multiple roles of macrophage scavenger receptors (MSR) in vivo: resistance to atherosclerosis and susceptibility to infection in MSR knockout mice. J Atheroscler Thromb 1997; 4: 1-11.
24 Saad AF, Virella G, Chassereau C. et al. OxLDL immune complexes activate complement and induce cytokine production by MonoMac 6 cells and human macrophages. J Lipid Res 2006; 47: 1975-1983.
25 Choi SH, Harkewicz R, Lee JH. et al. Lipoprotein accumulation in macrophages via toll-like receptor-4-dependent fluid phase uptake. Circ Res 2009; 104: 1355-1363.
26 Miller YI, Choi SH, Fang L. et al. Toll-like receptor-4 and lipoprotein accumulation in macrophages. Trends Cardiovasc Med 2009; 19: 227-232.
27 Xu XH, Shah PK, Faure E. et al. Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation 2001; 104: 3103-3108.
28 Mullick AE, Soldau K, Kiosses WB. et al. Increased endothelial expression of Toll-like receptor 2 at sites of disturbed blood flow exacerbates early atherogenic events. J Exp Med 2008; 205: 373-383.
29 Tabas I. Macrophage apoptosis in atherosclerosis: consequences on plaque progression and the role of endoplasmic reticulum stress. Antioxid Redox Signal 2009; 11: 2333-2339.
30 Tsukano H, Gotoh T, Endo M. et al. The endoplasmic reticulum stress-C/EBP homologous protein pathway-mediated apoptosis in macrophages contributes to the instability of atherosclerotic plaques. Arterioscler Thromb Vasc Biol 30: 1925-1932.
31 Llorente-Cortes V, Otero-Vinas M, Camino-Lopez S. et al. Aggregated low-density lipoprotein uptake induces membrane tissue factor procoagulant activity and microparticle release in human vascular smooth muscle cells. Circulation 2004; 110: 452-459.
32 Camino-Lopez S, Llorente-Cortes V, Sendra J. et al. Tissue factor induction by aggregated LDL depends on LDL receptor-related protein expression (LRP1) and Rho A translocation in human vascular smooth muscle cells. Cardiovasc Res 2007; 73: 208-216.
33 Han CI, Campbell GR, Campbell JH. Circulating bone marrow cells can contribute to neointimal formation. J Vasc Res 2001; 38: 113-119.
34 Padro T, Pena E, Garcia-Arguinzonis M. et al. Low-density lipoproteins impair migration of human coronary vascular smooth muscle cells and induce changes in the proteomic profile of myosin light chain. Cardiovasc Res 2008; 77: 211-220.
35 Badimon JJ, Santos-Gallego CG, Badimon L. [Importance of HDL cholesterol in atherothrombosis: how did we get here? Where are we going?]. Rev Esp Cardiol 2010; 63 (Suppl. 02) 20-35.
36 Choi BG, Vilahur G, Yadegar D. et al. The role of high-density lipoprotein cholesterol in the prevention and possible treatment of cardiovascular diseases. Curr Mol Med 2006; 6: 571-587.
37 Cimmino G, Ibanez B, Vilahur G. et al. Up-regulation of reverse cholesterol transport key players and rescue from global inflammation by ApoA-I (Milano). J Cell Mol Med 2009; 13: 3226-3235.
38 Stenvinkel P, Karimi M, Johansson S. et al. Impact of inflammation on epigenetic DNA methylation – a novel risk factor for cardiovascular disease?. J Intern Med 2007; 261: 488-499.
39 Sharma P, Kumar J, Garg G. et al. Detection of altered global DNA methylation in coronary artery disease patients. DNA Cell Biol 2008; 27: 357-365.
40 Vickers KC, Remaley AT. MicroRNAs in atherosclerosis and lipoprotein metabolism. Curr Opin Endocrinol Diabetes Obes 2010; 17: 150-155.
41 Harris TA, Yamakuchi M, Ferlito M. et al. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci USA 2008; 105: 1516-1521.
42 Zernecke A, Bidzhekov K, Noels H. et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal 2009; 2: ra81.
43 Bonauer A, Carmona G, Iwasaki M. et al. MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science 2009; 324: 1710-1713.
44 Bonauer A, Boon RA, Dimmeler S. Vascular microRNAs. Curr Drug Targets 2010; 11: 943-949.
45 Badimon L, Badimon JJ. Mechanisms of arterial thrombosis in nonparallel streamlines: platelet thrombi grow on the apex of stenotic severely injured vessel wall. Experimental study in the pig model. J Clin Invest 1989; 84: 1134-1144.
46 Molins B, Pena E, Padro T. et al. Glucose-regulated protein 78 and platelet deposition: effect of rosuvastatin. Arterioscler Thromb Vasc Biol 30: 1246-1252.
47 Yaron G, Brill A, Dashevsky O. et al. C-reactive protein promotes platelet adhesion to endothelial cells: a potential pathway in atherothrombosis. Br J Haematol 2006; 134: 426-431.
48 Molins B, Pena E, Vilahur G. et al. C-reactive protein isoforms differ in their effects on thrombus growth. Arterioscler Thromb Vasc Biol 2008; 28: 2239-2246.
49 Eisenhardt SU, Habersberger J, Murphy A. et al. Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques. Circ Res 2009; 105: 128-137.
50 Badimon L, Badimon JJ, Vilahur G. et al. Pathogenesis of the acute coronary syndromes and therapeutic implications. Pathophysiol Haemost Thromb 2002; 32: 225-231.
51 Parise L, Smyth S, Coller B. Platelet morphology, biochemistry, and function. McGraw-Hill Professional; New York: 2005
52 Viles-Gonzalez JF, Fuster V, Corti R. et al. Atherosclerosis regression and TP receptor inhibition: effect of S18886 on plaque size and composition--a magnetic resonance imaging study. Eur Heart J 2005; 26: 1557-1561.
53 Vilahur G, Casani L, Badimon L. A thromboxane A2/prostaglandin H2 receptor antagonist (S18886) shows high antithrombotic efficacy in an experimental model of stent-induced thrombosis. Thromb Haemost 2007; 98: 662-669.
54 Fuster V, Badimon L, Badimon JJ. et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med 1992; 326: 242-250.
55 Fuster V, Badimon L, Badimon JJ. et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med 1992; 326: 310-318.
56 Butt E, Gambaryan S, Gottfert N. et al. Actin binding of human LIM and SH3 protein is regulated by cGMP- and cAMP-dependent protein kinase phosphorylation on serine 146. J Biol Chem 2003; 278: 15601-15607.
57 Owens 3rd AP, Mackman N. Tissue factor and thrombosis: The clot starts here. Thromb Haemost 104: 432-439.
58 Hemker HC, van Rijn JL, Rosing J. et al. Platelet membrane involvement in blood coagulation. Blood Cells 1983; 9: 303-317.
59 Jennings LK. Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb Haemost 2009; 102: 248-257.
60 Libby P, Okamoto Y, Rocha VZ. et al. Inflammation in atherosclerosis: transition from theory to practice. Circ J 2010; 74: 213-220.
61 Sachais BS, Turrentine T, Dawicki McKenna JM. et al. Elimination of platelet factor 4 (PF4) from platelets reduces atherosclerosis in C57Bl/6 and apoE-/- mice. Thromb Haemost 2007; 98: 1108-1113.
62 Weyrich AS, Schwertz H, Kraiss LW. et al. Protein synthesis by platelets: historical and new perspectives. J Thromb Haemost 2009; 7: 241-246.
63 Lindemann S, Tolley ND, Dixon DA. et al. Activated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis. J Cell Biol 2001; 154: 485-490.
64 Weyrich AS, Denis MM, Schwertz H. et al. mTOR-dependent synthesis of Bcl-3 controls the retraction of fibrin clots by activated human platelets. Blood 2007; 109: 1975-1983.
65 Evangelista V, Manarini S, Di Santo A. et al. De novo synthesis of cyclooxygenase-1 counteracts the suppression of platelet thromboxane biosynthesis by aspirin. Circ Res 2006; 98: 593-595.
66 Mason KD, Carpinelli MR, Fletcher JI. et al. Programmed anuclear cell death delimits platelet life span. Cell 2007; 128: 1173-1186.
67 Langer HF, Gawaz M. Platelets in regenerative medicine. Basic Res Cardiol 2008; 103: 299-307.
68 Jin DK, Shido K, Kopp HG. et al. Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nat Med 2006; 12: 557-567.
69 Stellos K, Bigalke B, Langer H. et al. Expression of stromal-cell-derived factor-1 on circulating platelets is increased in patients with acute coronary syndrome and correlates with the number of CD34+ progenitor cells. Eur Heart J 2009; 30: 584-593.
70 Hristov M, Zernecke A, Bidzhekov K. et al. Importance of CXC chemokine receptor 2 in the homing of human peripheral blood endothelial progenitor cells to sites of arterial injury. Circ Res 2007; 100: 590-597.
71 Mause SF, Ritzel E, Liehn EA. et al. Platelet microparticles enhance the vasoregenerative potential of angiogenic early outgrowth cells after vascular injury. Circulation 122: 495-506.
72 Koenen RR, Weber C. Platelet-derived chemokines in vascular remodeling and atherosclerosis. Semin Thromb Hemost 36: 163-169.
73 Langer H, May AE, Daub K. et al. Adherent platelets recruit and induce differentiation of murine embryonic endothelial progenitor cells to mature endothelial cells in vitro. Circ Res 2006; 98: e2-10.
74 Seizer P, Schiemann S, Merz T. et al. CD36 and macrophage scavenger receptor a modulate foam cell formation via inhibition of lipid-laden platelet phagocytosis. Semin Thromb Hemost 36: 157-162.