3.2. Modelo teórico de la Propuesta
3.2.8.4. Integración de las acciones para contribuir a la formación
The aim of this thesis is to find new cellular biomarkers in whole blood, which improve the risk stratification of cardiovascular disease patients. Chapters 2 to 5 respectively investigate monocyte subsets, T cell subsets, neutrophil subsets and cytokines as potential biomarkers for cardiovascular disease, furthermore chapter 6 investigates the influence of smoking on circulating biomarkers in patients with cardiovascular disease.
Chapter 1 References
1. Levy D. Combating the epidemic of heart disease. JAMA 2012; 308(24): 2624–2625. doi:10.1001/
jama.2012.164971.
2. Moran AE et al. Temporal trends in ischemic heart disease mortality in 21 world regions, 1980 to 2010:
the Global Burden of Disease 2010 study. Circulation 2014; 129(14): 1483–1492. doi:10.1161/CIRCU- LATIONAHA.113.004042.
3. Murray CJL, Lopez AD. Measuring the global burden of disease. N Engl J Med 2013; 369(5): 448–457.
doi:10.1056/NEJMra1201534.
4. Lozano R et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990
and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380(9859): 2095–2128. doi:10.1016/S0140-6736(12)61728-0.
5. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS
Med 2006; 3(11): e442. doi:10.1371/journal.pmed.0030442.
6. Fuster V, Mearns BM. The CVD paradox: mortality vs prevalence. Nat Rev Cardiol 2009; 6(11): 669.
doi:10.1038/nrcardio.2009.187.
7. Laslett LJ et al. The worldwide environment of cardiovascular disease: prevalence, diagnosis, therapy,
and policy issues: a report from the American College of Cardiology. J Am Coll Cardiol 2012; 60(25 Suppl): S1–49. doi:10.1016/j.jacc.2012.11.002.
8. Nabel EG, Braunwald E. A tale of coronary artery disease and myocardial infarction. N Engl J Med
2012; 366(1): 54–63. doi:10.1056/NEJMra1112570.
9. Heidenreich PA et al. Forecasting the future of cardiovascular disease in the United States: a poli-
cy statement from the American Heart Association. Circulation 2011; 123(8): 933–944. doi:10.1161/ CIR.0b013e31820a55f5.
10. Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation 2005; 111(25): 3481–3488.
doi:10.1161/CIRCULATIONAHA.105.537878.
11. Davies MJ. Stability and instability: two faces of coronary atherosclerosis. The Paul Dudley White Lec-
ture 1995. Circulation 1996; 94(8): 2013–2020.
12. Stary HC. Macrophage foam cells in the coronary artery intima of human infants. Ann N Y Acad Sci
1985; 454: 5–8.
13. Stary HC. Evolution and progression of atherosclerotic lesions in coronary arteries of children and
young adults. Arteriosclerosis 1989; 9(1 Suppl): I19–32. Available at: http://europepmc.org/abstract/ MED/2912430.
14. Wentzel JJ et al. Endothelial shear stress in the evolution of coronary atherosclerotic plaque and vas-
cular remodelling: current understanding and remaining questions. Cardiovasc Res 2012; 96(2): 234– 243. doi:10.1093/cvr/cvs217.
15. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation 2004; 109(23 Suppl
1): III27–32. doi:10.1161/01.CIR.0000131515.03336.f8.
16. Dai G et al. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclero-
sis-susceptible and -resistant regions of human vasculature. Proc Natl Acad Sci U S A 2004; 101(41): 14871–14876. doi:10.1073/pnas.0406073101.
17. Nakashima Y et al. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the en-
Introduction
18. Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ
Res 2000; 87(10): 840–844.
19. Hink U et al. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 2001;
88(2): E14–22. doi:10.1161/01.RES.88.2.e14.
20. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340(2): 115–126. doi:10.1056/
NEJM199901143400207.
21. Skalen K et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature
2002; 417(6890): 750–754. doi:10.1038/nature00804.
22. Virmani R et al. Lessons from sudden coronary death: a comprehensive morphological classification
scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20(5): 1262–1275.
23. Steinberg D, Witztum JL. Oxidized low-density lipoprotein and atherosclerosis. Arterioscler Thromb
Vasc Biol 2010; 30(12): 2311–2316. doi:10.1161/ATVBAHA.108.179697.
24. Libby P et al. Progress and challenges in translating the biology of atherosclerosis. Nature 2011;
473(7347): 317–325. doi:10.1038/nature10146.
25. Cybulsky MI, Gimbrone MAJ. Endothelial expression of a mononuclear leukocyte adhesion molecule
during atherogenesis. Science 1991; 251(4995): 788–791. doi:10.1126/science.1990440.
26. Drexler H. Nitric oxide and coronary endothelial dysfunction in humans. Cardiovasc Res 1999; 43(3):
572–579.
27. Drexler H, Hornig B. Endothelial dysfunction in human disease. J Mol Cell Cardiol 1999; 31(1): 51–60.
doi:10.1006/jmcc.1998.0843.
28. Ley K et al. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Im-
munol 2007; 7(9): 678–689. doi:10.1038/nri2156.
29. De Villiers WJ, Smart EJ. Macrophage scavenger receptors and foam cell formation. J Leukoc Biol 1999;
66(5): 740–746.
30. Linton MF, Fazio S. Class A scavenger receptors, macrophages, and atherosclerosis. Curr Opin Lipidol
2001; 12(5): 489–495. doi:10.1097/00041433-200110000-00003.
31. Napoli C et al. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by mater-
nal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest 1997; 100(11): 2680–2690. doi:10.1172/JCI119813.
32. Stary HC. Lipid and macrophage accumulations in arteries of children and the development of athero-
sclerosis. Am J Clin Nutr 2000; 72(5 Suppl): 1297S–1306S.
33. O’Keefe JHJ et al. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically
normal. J Am Coll Cardiol 2004; 43(11): 2142–2146. doi:10.1016/j.jacc.2004.03.046.
34. Tabas I et al. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update
and therapeutic implications. Circulation 2007; 116(16): 1832–1844. doi:10.1161/CIRCULATIONA- HA.106.676890.
35. Hartiala O et al. Adolescence risk factors are predictive of coronary artery calcification at middle age:
the cardiovascular risk in young Finns study. J Am Coll Cardiol 2012; 60(15): 1364–1370. doi:10.1016/j. jacc.2012.05.045.
36. Stamler J et al. Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men
to long-term coronary, cardiovascular, and all-cause mortality and to longevity. JAMA 2000; 284(3): 311–318. doi:10.1001/jama.284.3.311.
Chapter 1
37. Lusis AJ. Atherosclerosis. Nature 2000; 407(6801): 233–241. doi:10.1038/35025203.
38. Dalager S et al. Artery-related differences in atherosclerosis expression: implications for atherogenesis
and dynamics in intima-media thickness. Stroke 2007; 38(10): 2698–2705. doi:10.1161/STROKEA- HA.107.486480.
39. Kolodgie FD et al. Is pathologic intimal thickening the key to understanding early plaque progression
in human atherosclerotic disease? Arterioscler Thromb Vasc Biol 2007; 27(5): 986–989. doi:10.1161/ ATVBAHA.0000258865.44774.41.
40. Myoishi M et al. Increased endoplasmic reticulum stress in atherosclerotic plaques associated with
acute coronary syndrome. Circulation 2007; 116(11): 1226–1233. doi:10.1161/CIRCULATIONA- HA.106.682054.
41. Seimon TA et al. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in mac-
rophages undergoing endoplasmic reticulum stress. Cell Metab 2010; 12(5): 467–482. doi:10.1016/j. cmet.2010.09.010.
42. Tabas I. Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol
2010; 10(1): 36–46. doi:10.1038/nri2675.
43. Gautier EL et al. Macrophage apoptosis exerts divergent effects on atherogenesis as a function of lesion
stage. Circulation 2009; 119(13): 1795–1804. doi:10.1161/CIRCULATIONAHA.108.806158.
44. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell 2011; 145(3): 341–355.
doi:10.1016/j.cell.2011.04.005.
45. Clarke MCH, Bennett MR. Cause or consequence: what does macrophage apoptosis do in atheroscle-
rosis? Arterioscler Thromb Vasc Biol 2009; 29(2): 153–155. doi:10.1161/ATVBAHA.108.179903.
46. Clarke MCH et al. Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability
in atherosclerosis. Nat Med 2006; 12(9): 1075–1080. doi:10.1038/nm1459.
47. Moreno PR et al. Neovascularization in human atherosclerosis. Circulation 2006; 113(18): 2245–2252.
doi:10.1161/CIRCULATIONAHA.105.578955.
48. Sluimer JC, Daemen MJ. Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis.
J Pathol 2009; 218(1): 7–29. doi:10.1002/path.2518.
49. Sluimer JC et al. Hypoxia, hypoxia-inducible transcription factor, and macrophages in human athero-
sclerotic plaques are correlated with intraplaque angiogenesis. J Am Coll Cardiol 2008; 51(13): 1258– 1265. doi:10.1016/j.jacc.2007.12.025.
50. Kumamoto M et al. Intimal neovascularization in human coronary atherosclerosis: its origin and
pathophysiological significance. Hum Pathol 1995; 26(4): 450–456. doi:10.1016/0046-8177(95)90148- 5.
51. Barger AC et al. Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A pos-
sible role in the pathophysiology of atherosclerosis. N Engl J Med 1984; 310(3): 175–177. doi:10.1056/ NEJM198401193100307.
52. Eriksson EE. Intravital microscopy on atherosclerosis in apolipoprotein e-deficient mice establishes
microvessels as major entry pathways for leukocytes to advanced lesions. Circulation 2011; 124(19): 2129–2138. doi:10.1161/CIRCULATIONAHA.111.030627.
53. Sluimer JC et al. Thin-walled microvessels in human coronary atherosclerotic plaques show incom-
plete endothelial junctions relevance of compromised structural integrity for intraplaque microvascu- lar leakage. J Am Coll Cardiol 2009; 53(17): 1517–1527. doi:10.1016/j.jacc.2008.12.056.
Introduction
349(24): 2316–2325. doi:10.1056/NEJMoa035655.
55. Glagov S et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med
1987; 316(22): 1371–1375. doi:10.1056/NEJM198705283162204.
56. Montalescot G et al. 2013 ESC guidelines on the management of stable coronary artery disease: the
Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013; 34(38): 2949–3003. doi:10.1093/eurheartj/eht296.
57. McGill HCJ et al. Effects of serum lipoproteins and smoking on atherosclerosis in young men and
women. The PDAY Research Group. Pathobiological Determinants of Atherosclerosis in Youth. Arte- rioscler Thromb Vasc Biol 1997; 17(1): 95–106.
58. Davies MJ. The pathophysiology of acute coronary syndromes. Heart 2000; 83(3): 361–366.
59. Hamm CW et al. ESC Guidelines for the management of acute coronary syndromes in patients pre-
senting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevatio. Eur Heart J 2011; 32(23): 2999–3054. doi:10.1093/eurheartj/ehr236.
60. Falk E et al. Update on acute coronary syndromes: the pathologists’ view. Eur Heart J 2013; 34(10):
719–728. doi:10.1093/eurheartj/ehs411.
61. Burke AP et al. Coronary risk factors and plaque morphology in men with coronary disease who died
suddenly. N Engl J Med 1997; 336(18): 1276–1282. doi:10.1056/NEJM199705013361802.
62. Newby AC. Matrix metalloproteinase inhibition therapy for vascular diseases. Vascul Pharmacol 2012;
56(5-6): 232–244. doi:10.1016/j.vph.2012.01.007.
63. Den Dekker WK et al. Mast cells induce vascular smooth muscle cell apoptosis via a toll-like receptor
4 activation pathway. Arterioscler Thromb Vasc Biol 2012; 32(8): 1960–1969. doi:10.1161/ATVBA- HA.112.250605.
64. Sato K et al. TRAIL-expressing T cells induce apoptosis of vascular smooth muscle cells in the athero-
sclerotic plaque. J Exp Med 2006; 203(1): 239–250. doi:10.1084/jem.20051062.
65. Boyle JJ et al. Tumor necrosis factor-alpha promotes macrophage-induced vascular smooth muscle cell
apoptosis by direct and autocrine mechanisms. Arterioscler Thromb Vasc Biol 2003; 23(9): 1553–1558. doi:10.1161/01.ATV.0000086961.44581.B7.
66. Van der Wal AC et al. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques
is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circula- tion 1994; 89(1): 36–44. doi:10.1161/01.CIR.89.1.36.
67. Kolodgie FD et al. The thin-cap fibroatheroma: a type of vulnerable plaque: the major precursor le-
sion to acute coronary syndromes. Curr Opin Cardiol 2001; 16(5): 285–292. doi:10.1097/00001573- 200109000-00006.
68. Gough PJ et al. Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-de-
ficient mice. J Clin Invest 2006; 116(1): 59–69. doi:10.1172/JCI25074.
69. Stone GW et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011;
364(3): 226–235. doi:10.1056/NEJMoa1002358.
70. Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Character-
istics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J 1983; 50(2): 127–134.
71. Burke AP et al. Effect of risk factors on the mechanism of acute thrombosis and sudden coronary death
Chapter 1
72. Goncalves I et al. Short communication: Dating components of human atherosclerotic plaques. Circ
Res 2010; 106(6): 1174–1177. doi:10.1161/CIRCRESAHA.109.211201.
73. Hansson GK. Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21(12):
1876–1890.
74. Libby P et al. Inflammation and atherosclerosis. Circulation 2002; 105(9): 1135–1143. doi:10.1161/
hc0902.104353.
75. Geissmann F et al. Blood monocytes consist of two principal subsets with distinct migratory proper-
ties. Immunity 2003; 19(1): 71–82. doi:10.1016/S1074-7613(03)00174-2.
76. Woollard KJ, Geissmann F. Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol 2010;
7(2): 77–86. doi:10.1038/nrcardio.2009.228.
77. Auffray C et al. Blood monocytes: development, heterogeneity, and relationship with dendrit-
ic cells. Annu Rev Immunol 2009; 27(December 2008): 669–692. doi:10.1146/annurev.immu- nol.021908.132557.
78. Auffray C et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling
behavior. Science 2007; 317(5838): 666–670. doi:10.1126/science.1142883.
79. Carlin LM et al. Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate
their disposal. Cell 2013; 153(2): 362–375. doi:10.1016/j.cell.2013.03.010.
80. Sunderkotter C et al. Subpopulations of mouse blood monocytes differ in maturation stage and inflam-
matory response. J Immunol 2004; 172(7): 4410–4417. doi:10.4049/jimmunol.172.7.4410.
81. Hilgendorf I et al. Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and repara-
tive phases in the infarcted myocardium. Circ Res 2014; 114(10): 1611–1622. doi:10.1161/CIRCRESA- HA.114.303204.
82. Yona S et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under
homeostasis. Immunity 2013; 38(1): 79–91. doi:10.1016/j.immuni.2012.12.001.
83. Swirski FK et al. Monocyte accumulation in mouse atherogenesis is progressive and proportional to
extent of disease. Proc Natl Acad Sci U S A 2006; 103(27): 10340–10345. doi:10.1073/pnas.0604260103.
84. Averill LE et al. Enhanced monocyte progenitor cell proliferation in bone marrow of hyperlipemic
swine. Am J Pathol 1989; 135(2): 369–377.
85. Tolani S et al. Hypercholesterolemia and reduced HDL-C promote hematopoietic stem cell proliferation
and monocytosis: studies in mice and FH children. Atherosclerosis 2013; 229(1): 79–85. doi:10.1016/j. atherosclerosis.2013.03.031.
86. Murphy AJ et al. ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte
accumulation in atherosclerotic lesions in mice. J Clin Invest 2011; 121(10): 4138–4149. doi:10.1172/ JCI57559.
87. Boring L et al. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initia-
tion of atherosclerosis. Nature 1998; 394(6696): 894–897. doi:10.1038/29788.
88. Soehnlein O et al. Distinct functions of chemokine receptor axes in the atherogenic mobiliza-
tion and recruitment of classical monocytes. EMBO Mol Med 2013; 5(3): 471–481. doi:10.1002/ emmm.201201717.
89. Combadiere C et al. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly-
6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation 2008; 117(13): 1649–1657. doi:10.1161/CIRCULATIONAHA.107.745091.
Introduction
oscler Thromb Vasc Biol 2010; 30(2): 186–192. doi:10.1161/ATVBAHA.109.198044.
91. Hanna RN et al. NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype
and increases atherosclerosis. Circ Res 2012; 110(3): 416–427. doi:10.1161/CIRCRESAHA.111.253377.
92. Hamers A a J et al. Bone marrow-specific deficiency of nuclear receptor Nur77 enhances atherosclero-
sis. Circ Res 2012; 110(3): 428–438. doi:10.1161/CIRCRESAHA.111.260760.
93. Chao LC et al. Bone marrow NR4A expression is not a dominant factor in the development of ath-
erosclerosis or macrophage polarization in mice. J Lipid Res 2013; 54(3): 806–815. doi:10.1194/jlr. M034157.
94. Hanna RN et al. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the
survival of Ly6C- monocytes. Nat Immunol 2011; 12(8): 778–785. doi:10.1038/ni.2063.
95. Van Furth R, Cohn ZA. The origin and kinetics of mononuclear phagocytes. J Exp Med 1968; 128(3):
415–435. doi:10.1084/jem.128.3.415.
96. Jakubzick C et al. Minimal differentiation of classical monocytes as they survey steady-state tissues and
transport antigen to lymph nodes. Immunity 2013; 39(3): 599–610. doi:10.1016/j.immuni.2013.08.007.
97. Guilliams M et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-
lived cells in the first week of life via GM-CSF. J Exp Med 2013; 210(10): 1977–1992. doi:10.1084/ jem.20131199.
98. Epelman S et al. Embryonic and adult-derived resident cardiac macrophages are maintained through
distinct mechanisms at steady state and during inflammation. Immunity 2014; 40(1): 91–104. doi:10.1016/j.immuni.2013.11.019.
99. Hashimoto D et al. Tissue-resident macrophages self-maintain locally throughout adult life with min-
imal contribution from circulating monocytes. Immunity 2013; 38(4): 792–804. doi:10.1016/j.immu- ni.2013.04.004.
100. Schulz C et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science
(80- ) 2012; 336(6077): 86–90. doi:10.1126/science.1219179.
101. Ginhoux F et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages.
Science 2010; 330(6005): 841–845. doi:10.1126/science.1194637.
102. Robbins CS et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis.
Nat Med 2013; 19(9): 1166–1172. doi:10.1038/nm.3258.
103. Aiello RJ et al. CCR2 receptor blockade alters blood monocyte subpopulations but does not affect atherosclerotic lesions in apoE(-/-) mice. Atherosclerosis 2010; 208(2): 370–375. doi:10.1016/j.athero- sclerosis.2009.08.017.
104. Calin MV et al. Effect of depletion of monocytes/macrophages on early aortic valve lesion in experi-
mental hyperlipidemia. Cell Tissue Res 2009; 336(2): 237–248. doi:10.1007/s00441-009-0765-2.
105. Guo J et al. Repopulation of apolipoprotein E knockout mice with CCR2-deficient bone marrow pro-
genitor cells does not inhibit ongoing atherosclerotic lesion development. Arterioscler Thromb Vasc Biol 2005; 25(5): 1014–1019. doi:10.1161/01.ATV.0000163181.40896.42.
106. Mills CD et al. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 2000; 164(12): 6166–
6173. doi:10.4049/jimmunol.164.12.6166.
107. Murray PJ et al. Macrophage activation and polarization: nomenclature and experimental guidelines.
Immunity 2014; 41(1): 14–20. doi:10.1016/j.immuni.2014.06.008.
108. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008; 8(12): 958–969. doi:10.1038/nri2788.
Chapter 1
109. Martinez FO et al. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol 2006; 177(10): 7303– 7311. doi:10.1016/S1077-9108(08)70760-6.
110. Wolfs IMJ et al. Differentiation factors and cytokines in the atherosclerotic plaque micro-environment
as a trigger for macrophage polarisation. Thromb Haemost 2011; 106(5): 763–771. doi:10.1160/TH11- 05-0320.
111. Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol
2011; 11(11): 723–737. doi:10.1038/nri3073.
112. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 2012; 122(3):
787–795. doi:10.1172/JCI59643.
113. Martinez FO et al. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 2009; 27: 451–483. doi:10.1146/annurev.immunol.021908.132532.
114. Bouhlel MA et al. PPARgamma activation primes human monocytes into alternative M2 macrophages
with anti-inflammatory properties. Cell Metab 2007; 6(2): 137–143. doi:10.1016/j.cmet.2007.06.010.
115. Kadl A et al. Identification of a novel macrophage phenotype that develops in response to atherogenic
phospholipids via Nrf2. Circ Res 2010; 107(6): 737–746. doi:10.1161/CIRCRESAHA.109.215715.
116. Ley K et al. Monocyte and macrophage dynamics during atherogenesis. Arterioscler Thromb Vasc Biol
2011; 31(7): 1506–1516. doi:10.1161/ATVBAHA.110.221127.
117. Mantovani A et al. Macrophage diversity and polarization in atherosclerosis: a question of balance. Arterioscler Thromb Vasc Biol 2009; 29(10): 1419–1423. doi:10.1161/ATVBAHA.108.180497.
118. Peled M, Fisher EA. Dynamic Aspects of Macrophage Polarization during Atherosclerosis Progression
and Regression. Front Immunol 2014; 5: 579. doi:10.3389/fimmu.2014.00579.
119. Amulic B et al. Neutrophil function: from mechanisms to disease. Annu Rev Immunol 2012; 30: 459–
489. doi:10.1146/annurev-immunol-020711-074942.
120. Mantovani A et al. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat
Rev Immunol 2011; 11(8): 519–531. doi:10.1038/nri3024.
121. Nathan C. Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 2006; 6(3): 173–182. doi:10.1038/nri1785.
122. Soehnlein O, Lindbom L. Phagocyte partnership during the onset and resolution of inflammation. Nat
Rev Immunol 2010; 10(6): 427–439. doi:10.1038/nri2779.
123. Luo HR, Loison F. Constitutive neutrophil apoptosis: mechanisms and regulation. Am J Hematol 2008;
83(4): 288–295. doi:10.1002/ajh.21078.
124. Soehnlein O. Multiple roles for neutrophils in atherosclerosis. Circ Res 2012; 110(6): 875–888. doi:10.1161/CIRCRESAHA.111.257535.
125. Drechsler M et al. Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation
2010; 122(18): 1837–1845. doi:10.1161/CIRCULATIONAHA.110.961714.
126. Rotzius P et al. Distinct infiltration of neutrophils in lesion shoulders in ApoE-/- mice. Am J Pathol
2010; 177(1): 493–500. doi:10.2353/ajpath.2010.090480.
127. Eriksson EE et al. Direct viewing of atherosclerosis in vivo: plaque invasion by leukocytes is initiated by
the endothelial selectins. FASEB J 2001; 15(7): 1149–1157. doi:10.1096/fj.00-0537com.
128. Pereira HA et al. CAP37, a neutrophil granule-derived protein stimulates protein kinase C activity in
endothelial cells. J Leukoc Biol 1996; 60(3): 415–422.
Introduction
endothelial monolayers. Microvasc Res 2003; 66(1): 38–48. doi:10.1016/S0026-2862(03)00010-4.
130. Taekema-Roelvink ME et al. Proteinase 3 enhances endothelial monocyte chemoattractant protein-1
production and induces increased adhesion of neutrophils to endothelial cells by upregulating intercel- lular cell adhesion molecule-1. J Am Soc Nephrol 2001; 12(5): 932–940.
131. Eiserich JP et al. Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science 2002; 296(5577):
2391–2394. doi:10.1126/science.1106830.
132. Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol 2005; 25(6): 1102–1111. doi:10.1161/01.ATV.0000163262.83456.6d.
133. Soehnlein O et al. Mechanisms underlying neutrophil-mediated monocyte recruitment. Blood 2009;
114(21): 4613–4623. doi:10.1182/blood-2009-06-221630.
134. Ionita MG et al. High neutrophil numbers in human carotid atherosclerotic plaques are associated with characteristics of rupture-prone lesions. Arterioscler Thromb Vasc Biol 2010; 30(9): 1842–1848. doi:10.1161/ATVBAHA.110.209296.
135. De Nooijer R et al. Lesional overexpression of matrix metalloproteinase-9 promotes intraplaque hem-
orrhage in advanced lesions but not at earlier stages of atherogenesis. Arterioscler Thromb Vasc Biol 2006; 26(2): 340–346. doi:10.1161/01.ATV.0000197795.56960.64.
136. Bobryshev Y V. Dendritic cells and their role in atherogenesis. Lab Invest 2010; 90(7): 970–984. doi:10.1038/labinvest.2010.94.
137. Lichtman AH. T cell costimulatory and coinhibitory pathways in vascular inflammatory diseases. Front Physiol 2012; 3(February): 18. doi:10.3389/fphys.2012.00018.
138. Hansson GK et al. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J
Pathol 1989; 135(1): 169–175. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?ar- tid=1880219&tool=pmcentrez&rendertype=abstract.
139. Zhou X et al. Evidence for a local immune response in atherosclerosis. CD4+ T cells infiltrate le-