Immunity, atherosclerosis and cardiovascular disease

BMC Medicine

Johan Frostegård¹ 

[1] Karolinska Institutet, Institute of Environmental Medicine, Unit of Immunology and Chronic Disease, Nobels väg 13, Stockholm, 171 77, Sweden

关键词: Inflammation;    B-cells;    T-cells;    Natural antibodies;    Phosholipids;    Cardiovascular disease;    Atherosclerosis;    Immunity;   

Others  :  857076
DOI  :  10.1186/1741-7015-11-117

 received in 2013-01-21, accepted in 2013-04-15,  发布年份 2013

【 摘 要 】

Atherosclerosis, the major cause of cardiovascular disease (CVD), is a chronic inflammatory condition with immune competent cells in lesions producing mainly pro-inflammatory cytokines. Dead cells and oxidized forms of low density lipoproteins (oxLDL) are abundant. The major direct cause of CVD appears to be rupture of atherosclerotic plaques. oxLDL has proinflammatory and immune-stimulatory properties, causes cell death at higher concentrations and contains inflammatory phospholipids with phosphorylcholine (PC) as an interesting epitope. Antibodies against PC (anti-PC) may be atheroprotective, one mechanism being anti-inflammatory. Bacteria and virus have been discussed, but it has been difficult to find direct evidence, and antibiotic trials have not been successful. Heat shock proteins could be one major target for atherogenic immune reactions. More direct causes of plaque rupture include pro-inflammatory cytokines, chemokines, and lipid mediators. To prove that inflammation is a cause of atherosclerosis and CVD, clinical studies with anti-inflammatory and/or immune-modulatory treatment are needed. The potential causes of immune reactions and inflammation in atherosclerosis and how inflammation can be targeted therapeutically to provide novel treatments for CVD are reviewed.

【 授权许可】

   
2013 Frostegård; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Gimbrone MA Jr, Topper JN, Nagel T, Anderson KR, Garcia-Cardena G: Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann N Y Acad Sci 2000, 902:230-239. discussion 239–240
• [2]Campbell KA, Lipinski MJ, Doran AC, Skaflen MD, Fuster V, McNamara CA: Lymphocytes and the adventitial immune response in atherosclerosis. Circ Res 2012, 110:889-900.
• [3]Frostegard J, Ulfgren AK, Nyberg P, Hedin U, Swedenborg J, Andersson U, Hansson GK: Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis 1999, 145:33-43.
• [4]Libby P, Ridker PM, Hansson GK: Progress and challenges in translating the biology of atherosclerosis. Nature 2011, 473:317-325.
• [5]Camejo G, Lalaguna F, Lopez F, Starosta R: Characterization and properties of a lipoprotein-complexing proteoglycan from human aorta. Atherosclerosis 1980, 35:307-320.
• [6]Tabas I, Williams KJ, Boren J: Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 2007, 116:1832-1844.
• [7]Frostegard J, Nilsson J, Haegerstrand A, Hamsten A, Wigzell H, Gidlund M: Oxidized low density lipoprotein induces differentiation and adhesion of human monocytes and the monocytic cell line U937. Proc Natl Acad Sci USA 1990, 87:904-908.
• [8]Frostegard J, Wu R, Giscombe R, Holm G, Lefvert AK, Nilsson J: Induction of T-cell activation by oxidized low density lipoprotein. Arterioscler Thromb 1992, 12:461-467.
• [9]Berliner JA, Territo MC, Sevanian A, Ramin S, Kim JA, Bamshad B, Esterson M, Fogelman AM: Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J Clin Invest 1990, 85:1260-1266.
• [10]Elinder LS, Dumitrescu A, Larsson P, Hedin U, Frostegard J, Claesson HE: Expression of phospholipase A2 isoforms in human normal and atherosclerotic arterial wall. Arterioscler Thromb Vasc Biol 1997, 17:2257-2263.
• [11]Atout R, Karabina SA, Dollet S, Carreras M, Payre C, Andre P, Lambeau G, Lotteau V, Ninio E, Perrin-Cocon L: Human group X secreted phospholipase A2 induces dendritic cell maturation through lipoprotein-dependent and -independent mechanisms. Atherosclerosis 2012, 222:367-374.
• [12]Huang YH, Schafer-Elinder L, Wu R, Claesson HE, Frostegard J: Lysophosphatidylcholine (LPC) induces proinflammatory cytokines by a platelet-activating factor (PAF) receptor-dependent mechanism. Clin Exp Immunol 1999, 116:326-331.
• [13]Goncalves I, Edsfeldt A, Ko NY, Grufman H, Berg K, Bjorkbacka H, Nitulescu M, Persson A, Nilsson M, Prehn C, Adamski J, Nilsson J: Evidence supporting a key role of Lp-PLA2-generated lysophosphatidylcholine in human atherosclerotic plaque inflammation. Arterioscler Thromb Vasc Biol 2012, 32:1505-1512.
• [14]Frostegard J, Huang YH, Ronnelid J, Schafer-Elinder L: Platelet-activating factor and oxidized LDL induce immune activation by a common mechanism. Arterioscler Thromb Vasc Biol 1997, 17:963-968.
• [15]Watson AD, Leitinger N, Navab M, Faull KF, Horkko S, Witztum JL, Palinski W, Schwenke D, Salomon RG, Sha W, Subbanagounder G, Fogelman AM, Berliner JA: Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/endothelial interactions and evidence for their presence in vivo. J Biol Chem 1997, 272:13597-13607.
• [16]Greig FH, Kennedy S, Spickett CM: Physiological effects of oxidized phospholipids and their cellular signaling mechanisms in inflammation. Free Radic Biol Med 2012, 52:266-280.
• [17]Miller YI, Choi SH, Wiesner P, Fang L, Harkewicz R, Hartvigsen K, Boullier A, Gonen A, Diehl CJ, Que X, Montano E, Shaw PX, Tsimikas S, Binder CJ, Witztum JL: Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ Res 2011, 108:235-248.
• [18]Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L: Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case–control study. Lancet 2004, 364:937-952.
• [19]Yanbaeva DG, Dentener MA, Creutzberg EC, Wesseling G, Wouters EF: Systemic effects of smoking. Chest 2007, 131:1557-1566.
• [20]Morrow JD, Frei B, Longmire AW, Gaziano JM, Lynch SM, Shyr Y, Strauss WE, Oates JA, Roberts LJ 2nd: Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers smoking as a cause of oxidative damage. N Engl J Med 1995, 332:1198-1203.
• [21]Penn A, Snyder CA: Inhalation of sidestream cigarette smoke accelerates development of arteriosclerotic plaques. Circulation 1993, 88:1820-1825.
• [22]Zhu BQ, Sun YP, Sievers RE, Isenberg WM, Glantz SA, Parmley WW: Passive smoking increases experimental atherosclerosis in cholesterol-fed rabbits. J Am Coll Cardiol 1993, 21:225-232.
• [23]Gairola CG, Drawdy ML, Block AE, Daugherty A: Sidestream cigarette smoke accelerates atherogenesis in apolipoprotein E−/− mice. Atherosclerosis 2001, 156:49-55.
• [24]Kunitomo M, Yamaguchi Y, Kagota S, Yoshikawa N, Nakamura K, Shinozuka K: Biochemical evidence of atherosclerosis progression mediated by increased oxidative stress in apolipoprotein E-deficient spontaneously hyperlipidemic mice exposed to chronic cigarette smoke. J Pharmacol Sci 2009, 110:354-361.
• [25]Frostegard J: Atherosclerosis in patients with autoimmune disorders. Arterioscler Thromb Vasc Biol 2005, 25:1776-1785.
• [26]Dimitriadis E, Griffin M, Owens D, Johnson A, Collins P, Tomkin GH: Oxidation of low-density lipoprotein in NIDDM: its relationship to fatty acid composition. Diabetologia 1995, 38:1300-1306.
• [27]Beckman JA, Goldfine AB, Gordon MB, Creager MA: Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation 2001, 103:1618-1623.
• [28]Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000, 404:787-790.
• [29]Laursen JB, Somers M, Kurz S, McCann L, Warnholtz A, Freeman BA, Tarpey M, Fukai T, Harrison DG: Endothelial regulation of vasomotion in apoE-deficient mice: implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation 2001, 103:1282-1288.
• [30]Iyer SS, Pulskens WP, Sadler JJ, Butter LM, Teske GJ, Ulland TK, Eisenbarth SC, Florquin S, Flavell RA, Leemans JC, Sutterwala FS: Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci USA 2009, 106:20388-20393.
• [31]Zheng Y, Gardner SE, Clarke MC: Cell death, damage-associated molecular patterns, and sterile inflammation in cardiovascular disease. Arterioscler Thromb Vasc Biol 2011, 31:2781-2786.
• [32]Anania C, Gustafsson T, Hua X, Su J, Vikstrom M, De Faire U, Heimburger M, Jogestrand T, Frostegard J: Increased prevalence of vulnerable atherosclerotic plaques and low levels of natural IgM antibodies against phosphorylcholine in patients with systemic lupus erythematosus. Arthritis Res Ther 2010, 12:R214.
• [33]Cederholm A, Svenungsson E, Jensen-Urstad K, Trollmo C, Ulfgren AK, Swedenborg J, Fei GZ, Frostegard J: Decreased binding of annexin v to endothelial cells: a potential mechanism in atherothrombosis of patients with systemic lupus erythematosus. Arterioscler Thromb Vasc Biol 2005, 25:198-203.
• [34]Paradies G, Petrosillo G, Paradies V, Ruggiero FM: Oxidative stress, mitochondrial bioenergetics, and cardiolipin in aging. Free Radic Biol Med 2010, 48:1286-1295.
• [35]Martin W, Hoffmeister M, Rotte C, Henze K: An overview of endosymbiotic models for the origins of eukaryotes, their ATP-producing organelles (mitochondria and hydrogenosomes), and their heterotrophic lifestyle. Biol Chem 2001, 382:1521-1539.
• [36]Su J, Hua X, Vikstrom M, Leander K, Gigante B, Hellenius ML, De Faire U, Frostegard J: Low levels of IgM antibodies to oxidized cardiolipin increase and high levels decrease risk of cardiovascular disease among 60-year olds: a prospective study. BMC Cardiovasc Disord 2013, 13:1.
• [37]Frostegard J: Low level natural antibodies against phosphorylcholine: a novel risk marker and potential mechanism in atherosclerosis and cardiovascular disease. Clin Immunol 2010, 134:47-54.
• [38]Binder CJ, Horkko S, Dewan A, Chang MK, Kieu EP, Goodyear CS, Shaw PX, Palinski W, Witztum JL, Silverman GJ: Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med 2003, 9:736-743.
• [39]Faria-Neto JR, Chyu KY, Li X, Dimayuga PC, Ferreira C, Yano J, Cercek B, Shah PK: Passive immunization with monoclonal IgM antibodies against phosphorylcholine reduces accelerated vein graft atherosclerosis in apolipoprotein E-null mice. Atherosclerosis 2006, 189:83-90.
• [40]Caligiuri G, Khallou-Laschet J, Vandaele M, Gaston AT, Delignat S, Mandet C, Kohler HV, Kaveri SV, Nicoletti A: Phosphorylcholine-targeting immunization reduces atherosclerosis. J Am Coll Cardiol 2007, 50:540-546.
• [41]Su J, Georgiades A, Wu R, Thulin T, De Faire U, Frostegard J: Antibodies of IgM subclass to phosphorylcholine and oxidized LDL are protective factors for atherosclerosis in patients with hypertension. Atherosclerosis 2006, 188:160-166.
• [42]Su J, Hua X, Concha H, Svenungsson E, Cederholm A, Frostegard J: Natural antibodies against phosphorylcholine as potential protective factors in SLE. Rheumatology (Oxford) 2008, 47:1144-1150.
• [43]De Faire U, Su J, Hua X, Frostegard A, Halldin M, Hellenius ML, Wikstrom M, Dahlbom I, Gronlund H, Frostegard J: Low levels of IgM antibodies to phosphorylcholine predict cardiovascular disease in 60-year old men: effects on uptake of oxidized LDL in macrophages as a potential mechanism. J Autoimmun 2010, 34:73-79.
• [44]Fiskesund R, Su J, Viksröm M, Faire U, Frostegård J: Phosphorylcholine antibodies of the Group I idiotype inhibit cell death and, at high levels, are strong protection markers for atherosclerosis development, particularly when combined with other antibodies against modified LDL. Results Immunol 2012, 2:13-18.
• [45]Gronwall C, Vas J, Silverman GJ: Protective roles of natural IgM antibodies. Front Immunol 2012, 3:66.
• [46]Agmon-Levin N, Bat-sheva PK, Barzilai O, Ram M, Lindeberg S, Frostegard J, Shoenfeld Y: Antitreponemal antibodies leading to autoantibody production and protection from atherosclerosis in Kitavans from Papua New Guinea. Ann N Y Acad Sci 2009, 1173:675-682.
• [47]Elkan AC, Sjoberg B, Kolsrud B, Ringertz B, Hafstrom I, Frostegard J: Gluten-free vegan diet induces decreased LDL and oxidized LDL levels and raised atheroprotective natural antibodies against phosphorylcholine in patients with rheumatoid arthritis: a randomized study. Arthritis Res Ther 2008, 10:R34.
• [48]Rahman I, Atout R, Pedersen NL, De Faire U, Frostegard J, Ninio E, Bennet AM, Magnusson PK: Genetic and environmental regulation of inflammatory CVD biomarkers Lp-PLA2 and IgM anti-PC. Atherosclerosis 2011, 218:117-122.
• [49]Rossmann A, Henderson B, Heidecker B, Seiler R, Fraedrich G, Singh M, Parson W, Keller M, Grubeck-Loebenstein B, Wick G: T-cells from advanced atherosclerotic lesions recognize hHSP60 and have a restricted T-cell receptor repertoire. Exp Gerontol 2008, 43:229-237.
• [50]Knoflach M, Kiechl S, Mayrl B, Kind M, Gaston JS, van der Zee R, Faggionato A, Mayr A, Willeit J, Wick G: T-cell reactivity against HSP60 relates to early but not advanced atherosclerosis. Atherosclerosis 2007, 195:333-338.
• [51]Xu Q, Dietrich H, Steiner HJ, Gown AM, Schoel B, Mikuz G, Kaufmann SH, Wick G: Induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat shock protein 65. Arterioscler Thromb 1992, 12:789-799.
• [52]Xu Q, Willeit J, Marosi M, Kleindienst R, Oberhollenzer F, Kiechl S, Stulnig T, Luef G, Wick G: Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis. Lancet 1993, 341:255-259.
• [53]Murshid A, Gong J, Calderwood SK: The role of heat shock proteins in antigen cross presentation. Front Immunol 2012, 3:63.
• [54]Tamura Y, Torigoe T, Kukita K, Saito K, Okuya K, Kutomi G, Hirata K, Sato N: Heat-shock proteins as endogenous ligands building a bridge between innate and adaptive immunity. Immunotherapy 2012, 4:841-852.
• [55]Ross R: Atherosclerosis–an inflammatory disease. N Engl J Med 1999, 340:115-126.
• [56]Frostegard J, Kjellman B, Gidlund M, Andersson B, Jindal S, Kiessling R: Induction of heat shock protein in monocytic cells by oxidized low density lipoprotein. Atherosclerosis 1996, 121:93-103.
• [57]Frostegard J, Lemne C, Andersson B, van der Zee R, Kiessling R, De Faire U: Association of serum antibodies to heat-shock protein 65 with borderline hypertension. Hypertension 1997, 29:40-44.
• [58]Pockley AG, Georgiades A, Thulin T, De Faire U, Frostegard J: Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension. Hypertension 2003, 42:235-238.
• [59]Rosenfeld ME, Campbell LA: Pathogens and atherosclerosis: update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis. Thromb Haemost 2011, 106:858-867.
• [60]Shor A, Kuo CC, Patton DL: Detection of Chlamydia pneumoniae in coronary arterial fatty streaks and atheromatous plaques. S Afr Med J 1992, 82:158-161.
• [61]Saikku P, Leinonen M, Mattila K, Ekman MR, Nieminen MS, Makela PH, Huttunen JK, Valtonen V: Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 1988, 2:983-986.
• [62]Puolakkainen M, Kuo CC, Shor A, Wang SP, Grayston JT, Campbell LA: Serological response to Chlamydia pneumoniae in adults with coronary arterial fatty streaks and fibrolipid plaques. J Clin Microbiol 1993, 31:2212-2214.
• [63]Saikku P, Leinonen M, Tenkanen L, Linnanmaki E, Ekman MR, Manninen V, Manttari M, Frick MH, Huttunen JK: Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart Study. Ann Intern Med 1992, 116:273-278.
• [64]O’Connor CM, Dunne MW, Pfeffer MA, Muhlestein JB, Yao L, Gupta S, Benner RJ, Fisher MR, Cook TD: Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA 2003, 290:1459-1466.
• [65]Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB, Cohen JD, Rogers WJ, Crouse JR, Borrowdale SL, Schron E, Knirsch C: Azithromycin for the secondary prevention of coronary events. N Engl J Med 2005, 352:1637-1645.
• [66]Cannon CP, Braunwald E, McCabe CH, Grayston JT, Muhlestein B, Giugliano RP, Cairns R, Skene AM: Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med 2005, 352:1646-1654.
• [67]Lockhart PB, Bolger AF, Papapanou PN, Osinbowale O, Trevisan M, Levison ME, Taubert KA, Newburger JW, Gornik HL, Gewitz MH, Wilson WR, Smith SC Jr, Baddour LM: American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, Council on Epidemiology and Prevention, Council on Peripheral Vascular Disease, and Council on Clinical Cardiology: Periodontal disease and atherosclerotic vascular disease: does the evidence support an independent association?: a scientific statement from the American Heart Association. Circulation 2012, 125:2520-2544.
• [68]Fateh-Moghadam S, Bocksch W, Wessely R, Jager G, Hetzer R, Gawaz M: Cytomegalovirus infection status predicts progression of heart-transplant vasculopathy. Transplantation 2003, 76:1470-1474.
• [69]Melnick JL, Hu C, Burek J, Adam E, DeBakey ME: Cytomegalovirus DNA in arterial walls of patients with atherosclerosis. J Med Virol 1994, 42:170-174.
• [70]Streblow DN, Soderberg-Naucler C, Vieira J, Smith P, Wakabayashi E, Ruchti F, Mattison K, Altschuler Y, Nelson JA: The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle cell migration. Cell 1999, 99:511-520.
• [71]Mach F, Sukhova GK, Michetti M, Libby P, Michetti P: Influence of Helicobacter pylori infection during atherogenesis in vivo in mice. Circ Res 2002, 90:E1-E4.
• [72]Stone AF, Mendall MA, Kaski JC, Edger TM, Risley P, Poloniecki J, Camm AJ, Northfield TC: Effect of treatment for Chlamydia pneumoniae and Helicobacter pylori on markers of inflammation and cardiac events in patients with acute coronary syndromes: South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA). Circulation 2002, 106:1219-1223.
• [73]Volzke H, Wolff B, Ludemann J, Guertler L, Kramer A, John U, Felix SB: Seropositivity for anti-Borrelia IgG antibody is independently associated with carotid atherosclerosis. Atherosclerosis 2006, 184:108-112.
• [74]Koren O, Spor A, Felin J, Fak F, Stombaugh J, Tremaroli V, Behre CJ, Knight R, Fagerberg B, Ley RE, Backhed F: Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc Natl Acad Sci USA 2011, 108:4592-4598.
• [75]Amar J, Lange C, Payros G, Garret C, Chabo C, Lantieri O, Courtney M, Marre M, Charles MA, Balkau B, Burcelin R: Blood microbiota dysbiosis is associated with the onset of cardiovascular events in a large general population: the d.e.s.I.R. Study. PLoS One 2013, 8:e54461.
• [76]Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, Didonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ: Hazen. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med: SL; 2013.
• [77]Clark SE, Weiser JN: Microbial modulation of host immunity with the small molecule phosphorylcholine. Infect Immun 2013, 81:392-401.
• [78]Elkind MS: Infectious burden: a new risk factor and treatment target for atherosclerosis. Infect Disord Drug Targets 2012, 10:84-90.
• [79]Haeggstrom JZ, Funk CD: Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease. Chem Rev 2011, 111:5866-5898.
• [80]Qiu H, Gabrielsen A, Agardh HE, Wan M, Wetterholm A, Wong CH, Hedin U, Swedenborg J, Hansson GK, Samuelsson B, Paulsson-Berne G, Haeggström JZ: Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Proc Natl Acad Sci USA 2006, 103:8161-8166.
• [81]Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA Jr, Jansen-McWilliams L, D’Agostino RB, Kuller LH: Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997, 145:408-415.
• [82]Tyrrell PN, Beyene J, Feldman BM, McCrindle BW, Silverman ED, Bradley TJ: Rheumatic disease and carotid intima-media thickness a systematic review and meta-analysis. Arterioscler Thromb Vasc Biol 2010, 30:1014-1026.
• [83]Mayerl C, Lukasser M, Sedivy R, Niederegger H, Seiler R, Wick G: Atherosclerosis research from past to present–on the track of two pathologists with opposing views, Carl von Rokitansky and Rudolf Virchow. Virchows Arch 2006, 449:96-103.
• [84]Schwartz CJ, Mitchell JR: Cellular infiltration of the human arterial adventitia associated with atheromatous plaques. Circulation 1962, 26:73-78.
• [85]Houtkamp MA, De Boer OJ, van der Loos CM, van der Wal AC, Becker AE: Adventitial infiltrates associated with advanced atherosclerotic plaques: structural organization suggests generation of local humoral immune responses. J Pathol 2001, 193:263-269.
• [86]Stenmark KR, Yeager ME, El Kasmi KC, Nozik-Grayck E, Gerasimovskaya EV, Li M, Riddle SR, Frid MG: The adventitia: essential regulator of vascular wall structure and function. Annu Rev Physiol 2013, 75:23-47.
• [87]Moos MP, John N, Grabner R, Nossmann S, Gunther B, Vollandt R, Funk CD, Kaiser B, Habenicht AJ: The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2005, 25:2386-2391.
• [88]Smith E, Prasad KM, Butcher M, Dobrian A, Kolls JK, Ley K, Galkina E: Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice. Circulation 2010, 121:1746-1755.
• [89]Kolodgie FD, Gold HK, Burke AP, Fowler DR, Kruth HS, Weber DK, Farb A, Guerrero LJ, Hayase M, Kutys R, Narula J, Finn AV, Virmani R: Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 2003, 349:2316-2325.
• [90]Falk E, Nakano M, Bentzon JF, Finn AV, Virmani R: Update on acute coronary syndromes: the pathologists’ view. Eur Heart J 2013, 34:719-728.
• [91]David AR, Kershaw A, Heagerty A: Atherosclerosis and diet in ancient Egypt. Lancet 2012, 375:718-719.
• [92]Murphy WA Jr, Nedden DD, Gostner P, Knapp R, Recheis W, Seidler H: The iceman: discovery and imaging. Radiology 2003, 226:614-629.
• [93]Rollo F, Ubaldi M, Ermini L, Marota I: Otzi’s last meals: DNA analysis of the intestinal content of the Neolithic glacier mummy from the Alps. Proc Natl Acad Sci USA 2002, 99:12594-12599.
• [94]Keller A, Graefen A, Ball M, Matzas M, Boisguerin V, Maixner F, Leidinger P, Backes C, Khairat R, Forster M, Stade B, Franke A, Mayer J, Spangler J, McLaughlin S, Shah M, Lee C, Harkins TT, Sartori A, Moreno-Estrada A, Henn B, Sikora M, Semino O, Chiaroni J, Rootsi S, Myres NM, Cabrera VM, Underhill PA, Bustamante CD, Vigl EE: New insights into the Tyrolean Iceman’s origin and phenotype as inferred by whole-genome sequencing. Nat Commun 2012, 3:698.
• [95]Thompson RC, Allam AH, Lombardi GP, Wann LS, Sutherland ML, Sutherland JD, Soliman MA, Frohlich B, Mininberg DT, Monge JM, Vallodolid CM, Cox SL, Abd El-Maksoud G, Badr I, Miyamoto MI, El-Halim Nur El-Din A, Narula J, Finch CE, Thomas GS: Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations. Lancet 2013, 381:1211-1222.
• [96]Lindeberg S, Lundh B: Apparent absence of stroke and ischaemic heart disease in a traditional Melanesian island: a clinical study in Kitava. J Intern Med 1993, 233:269-275.
• [97]Frostegard J, Tao W, Georgiades A, Rastam L, Lindblad U, Lindeberg S: Atheroprotective natural anti-phosphorylcholine antibodies of IgM subclass are decreased in Swedish controls as compared to non-westernized individuals from New Guinea. Nutr Metab (Lond) 2007, 4:7.
• [98]Blanco DR, Champion CI, Dooley A, Cox DL, Whitelegge JP, Faull K, Lovett MA: A monoclonal antibody that conveys in vitro killing and partial protection in experimental syphilis binds a phosphorylcholine surface epitope of Treponema pallidum. Infect Immun 2005, 73:3083-3095.
• [99]Lemogoum D, Ngatchou W, Janssen C, Leeman M, Van Bortel L, Boutouyrie P, Degaute JP, Van de Borne P: Effects of hunter-gatherer subsistence mode on arterial distensibility in Cameroonian pygmies. Hypertension 2012, 60:123-128.
• [100]Burger O, Baudisch A, Vaupel JW: Human mortality improvement in evolutionary context. Proc Natl Acad Sci USA 2012, 109:18210-18214.
• [101]McCullagh KG: Arteriosclerosis in the African elephant. I. Intimal atherosclerosis and its possible causes. Atherosclerosis 1972, 16:307-335.
• [102]Ghittoni R, Napolitani G, Benati D, Ulivieri C, Patrussi L, Laghi Pasini F, Lanzavecchia A, Baldari CT: Simvastatin inhibits the MHC class II pathway of antigen presentation by impairing Ras superfamily GTPases. Eur J Immunol 2006, 36:2885-2893.
• [103]Wang CY, Liu PY, Liao JK: Pleiotropic effects of statin therapy: molecular mechanisms and clinical results. Trends Mol Med 2008, 14:37-44.
• [104]Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ, JUPITER Study Group: Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008, 359:2195-2207.
• [105]Ridker PM: Moving beyond JUPITER: will inhibiting inflammation reduce vascular event rates? Curr Atheroscler Rep 2013, 15:295.
• [106]Micha R, Imamura F, Wyler Von Ballmoos M, Solomon DH, Hernan MA, Ridker PM, Mozaffarian D: Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol 2011, 108:1362-1370.
• [107]Bulgarelli A, Martins Dias AA, Caramelli B, Maranhao RC: Treatment with methotrexate inhibits atherogenesis in cholesterol-fed rabbits. J Cardiovasc Pharmacol 2012, 59:308-314.
• [108]Krishnan E, Lingala VB, Singh G: Declines in mortality from acute myocardial infarction in successive incidence and birth cohorts of patients with rheumatoid arthritis. Circulation 2004, 110:1774-1779.
• [109]Bernatsky S, Hudson M, Suissa S: Anti-rheumatic drug use and risk of hospitalization for congestive heart failure in rheumatoid arthritis. Rheumatology (Oxford) 2005, 44:677-680.
• [110]Qamar A, Rader DJ: Effect of interleukin 1beta inhibition in cardiovascular disease. Curr Opin Lipidol 2012, 23:548-553.
• [111]Subbanagounder G, Leitinger N, Shih PT, Faull KF, Berliner JA: Evidence that phospholipid oxidation products and/or platelet-activating factor play an important role in early atherogenesis: in vitro and in vivo inhibition by WEB 2086. Circ Res 1999, 85:311-318.
• [112]Ewing MM, De Vries MR, Nordzell M, Pettersson K, De Boer HC, Van Zonneveld AJ, Frostegard J, Jukema JW, Quax PH: Annexin A5 therapy attenuates vascular inflammation and remodeling and improves endothelial function in mice. Arterioscler Thromb Vasc Biol 2011, 31:95-101.
• [113]O’Donoghue ML, Braunwald E, White HD, Serruys P, Steg PG, Hochman J, Maggioni AP, Bode C, Weaver D, Johnson JL, Cicconetti G, Lukas MA, Tarka E, Cannon CP: Study design and rationale for the Stabilization of pLaques usIng Darapladib-Thrombolysis in Myocardial Infarction (SOLID-TIMI 52) trial in patients after an acute coronary syndrome. Am Heart J 2011, 162:613-619.
• [114]Palinski W, Miller E, Witztum JL: Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. Proc Natl Acad Sci USA 1995, 92:821-825.
• [115]Fredrikson GN, Soderberg I, Lindholm M, Dimayuga P, Chyu KY, Shah PK, Nilsson J: Inhibition of atherosclerosis in apoE-null mice by immunization with apoB-100 peptide sequences. Arterioscler Thromb Vasc Biol 2003, 23:879-884.
• [116]Strom A, Fredrikson GN, Schiopu A, Ljungcrantz I, Soderberg I, Jansson B, Carlsson R, Hultgardh-Nilsson A, Nilsson J: Inhibition of injury-induced arterial remodelling and carotid atherosclerosis by recombinant human antibodies against aldehyde-modified apoB-100. Atherosclerosis 2007, 190:298-305.
• [117]Schiopu A, Bengtsson J, Soderberg I, Janciauskiene S, Lindgren S, Ares MP, Shah PK, Carlsson R, Nilsson J, Fredrikson GN: Recombinant human antibodies against aldehyde-modified apolipoprotein B-100 peptide sequences inhibit atherosclerosis. Circulation 2004, 110:2047-2052.
• [118]BioInvent announces data from BI-204 phase IIa study on stable atherosclerotic vascular disease. 2012. http://www.news-medical.net/news/20120711/BioInvent-announces-data-from-BI-204-phase-IIa-study-on-stable-atherosclerotic-vascular-disease.aspx webcite
• [119]Chen Y, Khanna S, Goodyear CS, Park YB, Raz E, Thiel S, Gronwall C, Vas J, Boyle DL, Corr M, Kono DH, Silverman GJ: Regulation of dendritic cells and macrophages by an anti-apoptotic cell natural antibody that suppresses TLR responses and inhibits inflammatory arthritis. J Immunol 2009, 183:1346-1359.
• [120]Nicoletti A, Kaveri S, Caligiuri G, Bariety J, Hansson GK: Immunoglobulin treatment reduces atherosclerosis in apo E knockout mice. J Clin Invest 1998, 102:910-918.
• [121]Long J, Lin J, Yang X, Yuan D, Wu J, Li T, Cao R, Liu J: Nasal immunization with different forms of heat shock protein-65 reduced high-cholesterol-diet-driven rabbit atherosclerosis. Int Immunopharmacol 2012, 13:82-87.
• [122]Jun L, Jie L, Dongping Y, Xin Y, Taiming L, Rongyue C, Jie W, Jingjing L: Effects of nasal immunization of multi-target preventive vaccines on atherosclerosis. Vaccine 2012, 30:1029-1037.
• [123]Klingenberg R, Ketelhuth DF, Strodthoff D, Gregori S, Hansson GK: Subcutaneous immunization with heat shock protein-65 reduces atherosclerosis in Apoe(−)/(−) mice. Immunobiology 2012, 217:540-547.
• [124]Li J, Zhao X, Zhang S, Wang S, Du P, Qi G: ApoB-100 and HSP60 peptides exert a synergetic role in inhibiting early atherosclerosis in immunized ApoE-null mice. Protein Pept Lett 2011, 18:733-740.