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 Cardiovascular Disorders

Johan Frostegård²  Ulf de Faire¹  Mai-Lis Hellenius⁴  Bruna Gigante³  Karin Leander³  Max Vikström³  Xiang Hua²  Jun Su² 

[1] Department of Cardiology, Karolinska University Hospital, Solna, Sweden;Institute of Environmental Medicine, Unit of Immunology and Chronic Disease, Karolinska Institutet, 17177 Stockholm, Stockholm, Sweden;Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden;Department of Medicine, Karolinska University Hospital, Solna, Sweden

关键词: Antibodies;    Oxidation;    Cardiolipin;    Cardiovascular disease;   

Others  :  857917
DOI  :  10.1186/1471-2261-13-1

 received in 2012-11-06, accepted in 2012-11-23,  发布年份 2013

【 摘 要 】

Background

Antibodies against cardiolipin (aCL) are associated with increased risk of cardiovascular disease (CVD). We here determine the role of antibodies against oxidized CL (aOxCL).

Methods

One third of sixty-year olds from the Stockholm County were screened (2039 men, 2193 women), where 211 incident CVD-cases and 633 age- and sex-matched controls were identified (5–7 year follow-up). Antibodies were determined by ELISA and uptake of oxLDL in macrophages by FACScan.

Results

IgM aOxCL was lower among CVD cases than controls (p=0.024). aOxCL-levels were divided in quartiles with the highest quartile set as the reference group. After adjustment for smoking, BMI, type II diabetes, hypercholesterolaemia and hypertension, an increased risk was determined in the lowest quartile of IgM aOxCL (OR: 1.80, CI: 1.12–2.91, p=0.0159); OR for men in the lowest quartile was 2.46 (CI 1.34–4.53, p=0.0037) for CVD and for stroke: 12.28 (CI: 1.48-101.77, p=0.02). IgG aOxCL levels did not differ between quartiles in CVD-risk. High levels of IgM aOxCL (reaching significance above 86th) and IgG aOxCL (above 95th percentile) were associated with decreased risk of CVD (OR: 0.485, CI: 0.283-0.829; p=0.0082 and OR: 0.23, CI: 0.07-0.69; p=0.0091). aCL were not associated with CVD. oxCL but not CL competed out uptake of OxLDL in macrophages, and aOxLDL recognized oxCL but not CL. In contrast to aCL, aOxCL was not dependent on co-factor Beta2-glycoprotein-I.

Conclusions

aOxCL is a novel risk/protection marker for CVD, with therapeutic implications. OxCL competes with oxLDL for uptake in macrophages and the possibility that aOxCL inhibits such uptake by interfering with same or similar epitopes in oxCL and oxLDL should be further studied.

【 授权许可】

   
2013 Su et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]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.
• [2]Ridker PM, Stampfer MJ, Rifai N: Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. Jama 2001, 285:2481-2485.
• [3]Zalewski A, Nelson JJ, Hegg L, Macphee C: Lp-PLA2: a new kid on the block. Clin Chem 2006, 52:1645-1650.
• [4]Caidahl K, Hartford M, Karlsson T, Herlitz J, Pettersson K, de Faire U, Frostegard J: IgM-phosphorylcholine autoantibodies and outcome in acute coronary syndromes. Int J Cardiol 2012.
• [5]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.
• [6]Fiskesund R, Stegmayr B, Hallmans G, Vikstrom M, Weinehall L, de Faire U, Frostegard J: Low levels of antibodies against phosphorylcholine predict development of stroke in a population-based study from northern Sweden. Stroke 2010, 41:607-612.
• [7]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.
• [8]Sjoberg BG, Su J, Dahlbom I, Gronlund H, Wikstrom M, Hedblad B, Berglund G, de Faire U, Frostegard J: Low levels of IgM antibodies against phosphorylcholine-A potential risk marker for ischemic stroke in men. Atherosclerosis 2009, 203:528-532.
• [9]Paradies G, Petrosillo G, Paradies V, Ruggiero FM: Oxidative stress, mitochondrial bioenergetics, and cardiolipin in aging. Free Radic Biol Med 2010, 48:1286-1295.
• [10]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.
• [11]Frostegard J: Atherosclerosis in patients with autoimmune disorders. Arterioscler Thromb Vasc Biol 2005, 25:1776-1785.
• [12]Halldin M, Rosell M, de Faire U, Hellenius ML: The metabolic syndrome: prevalence and association to leisure-time and work-related physical activity in 60-year-old men and women. Nutr Metab Cardiovasc Dis 2007, 17:349-357.
• [13]Carlsson AC, Wandell PE, de Faire U, Hellenius ML: Risk factors associated with newly diagnosed high blood pressure in men and women. Am J Hypertens 2008, 21:771-777.
• [14]Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J: A new equation to estimate glomerular filtration rate. Ann Intern Med 2009, 150:604-612.
• [15]Bianda N, Di Valentino M, Periat D, Segatto JM, Oberson M, Moccetti M, Sudano I, Santini P, Limoni C, Froio A, et al.: Progression of human carotid and femoral atherosclerosis: a prospective follow-up study by magnetic resonance vessel wall imaging. Eur Heart J 2011, 33:230-237.
• [16]Schlame M: Cardiolipin synthesis for the assembly of bacterial and mitochondrial membranes. J Lipid Res 2008, 49:1607-1620.
• [17]Horkko S, Miller E, Dudl E, Reaven P, Curtiss LK, Zvaifler NJ, Terkeltaub R, Pierangeli SS, Branch DW, Palinski W, Witztum JL: Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein. J Clin Investig 1996, 98:815-825.
• [18]Kagan VE, Tyurin VA, Jiang J, Tyurina YY, Ritov VB, Amoscato AA, Osipov AN, Belikova NA, Kapralov AA, Kini V, et al.: Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors. Nat Chem Biol 2005, 1:223-232.
• [19]Bayir H, Fadeel B, Palladino MJ, Witasp E, Kurnikov IV, Tyurina YY, Tyurin VA, Amoscato AA, Jiang J, Kochanek PM, et al.: Apoptotic interactions of cytochrome c: redox flirting with anionic phospholipids within and outside of mitochondria. Biochim Biophys Acta 2006, 1757:648-659.
• [20]Macchioni L, Corazzi T, Davidescu M, Francescangeli E, Roberti R, Corazzi L: Cytochrome c redox state influences the binding and release of cytochrome c in model membranes and in brain mitochondria. Mol Cell Biochem 2010, 341:149-157.
• [21]Gronlund H, Hallmans G, Jansson JH, Boman K, Wikstrom M, de Faire U, Frostegard J: Low levels of IgM antibodies against phosphorylcholine predict development of acute myocardial infarction in a population-based cohort from northern Sweden. Eur J Cardiovasc Prev Rehabil 2009, 16:382-386.
• [22]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.
• [23]Horkko S, Miller E, Branch DW, Palinski W, Witztum JL: The epitopes for some antiphospholipid antibodies are adducts of oxidized phospholipid and beta2 glycoprotein 1 (and other proteins). Proc Natl Acad Sci U S A 1997, 94:10356-10361.
• [24]Harris EN, Gharavi AE, Boey ML, Patel BM, Mackworth-Young CG, Loizou S, Hughes GR: Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983, 2:1211-1214.
• [25]Hamsten A, Norberg R, Bjorkholm M, de Faire U, Holm G: Antibodies to cardiolipin in young survivors of myocardial infarction: an association with recurrent cardiovascular events. Lancet 1986, 1:113-116.
• [26]Bili A, Moss AJ, Francis CW, Zareba W, Watelet LF, Sanz I: Anticardiolipin antibodies and recurrent coronary events: a prospective study of 1150 patients. Thrombogenic Factors, and Recurrent Coronary Events Investigators. Circulation 2000, 102:1258-1263.
• [27]Svenungsson E, Jensen-Urstad K, Heimburger M, Silveira A, Hamsten A, de Faire U, Witztum JL, Frostegard J: Risk factors for cardiovascular disease in systemic lupus erythematosus. Circulation 2001, 104:1887-1893.
• [28]Vaarala O, Alfthan G, Jauhiainen M, Leirisalo-Repo M, Aho K, Palosuo T: Crossreaction between antibodies to oxidised low-density lipoprotein and to cardiolipin in systemic lupus erythematosus. Lancet 1993, 341:923-925.
• [29]Deguchi H, Fernandez JA, Hackeng TM, Banka CL, Griffin JH: Cardiolipin is a normal component of human plasma lipoproteins. Proc Natl Acad Sci U S A 2000, 97:1743-1748.
• [30]Febbraio M, Podrez EA, Smith JD, Hajjar DP, Hazen SL, Hoff HF, Sharma K, Silverstein RL: Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J Clin Invest 2000, 105:1049-1056.
• [31]Moore KJ, Freeman MW: Scavenger receptors in atherosclerosis: beyond lipid uptake. Arterioscler Thromb Vasc Biol 2006, 26:1702-1711.
• [32]Tuominen A, Miller YI, Hansen LF, Kesaniemi YA, Witztum JL, Horkko S: A natural antibody to oxidized cardiolipin binds to oxidized low-density lipoprotein, apoptotic cells, and atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2006, 26:2096-2102.
• [33]Gronwall C, Vas J, Silverman GJ: Protective roles of natural IgM antibodies. Front Immunol 2012, 3:66.