Oxidized low-density lipoprotein and β2-glycoprotein I in patients with systemic lupus erythematosus and increased carotid intima-media thickness: implications in autoimmune-mediated atherosclerosis

Abstract

Oxidative stress and LDL modification (oxLDL) are early pro-atherogenic events. OxLDL binds β2GPI producing immunogenic oxLDL/β2GPI complexes. Antibodies to these complexes have been associated with arterial thrombosis in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Circulating oxLDL/β2GPI complexes, IgG and IgM antibodies to these complexes were measured by ELISA in 30 SLE patients asymptomatic for cardiovascular disease (mean age 31 years) and 27 age/sex matched healthy controls. Carotid intima-media thickness (IMT) was measured by ultrasound in all patients and controls. Forty-seven percent of SLE presented plaques (median IMT of 0.65 ± 0.12 mm) while only 7% of the controls had plaques (median IMT of 0.50 ± 0.04 mm, P < 0.001). Median optical density (OD_450nm) for oxLDL/β2GPI complexes in SLE was 0.244 ± 0.07, higher than controls (0.174 ± 0.09, P < 0.001). Median OD for IgG anti-oxLDL/β2GPI antibodies was also higher in SLE (0.297 ± 0.26) compared to controls (0.194 ± 0.07, P < 0.001) while the median OD for IgM antibodies in SLE (0.444 ± 0.46) was not different than controls (0.326 ± 0.22, P = 0.267). There was no correlation between IMT and oxLDL/β2GPI complexes, IgG or IgM antibodies, possibly reflecting the complex interrelationship between these serologic elements and tissue factors in the arterial wall. These results support the hypothesis that oxLDL/β2GPI complexes and IgG (not IgM) anti-oxLDL/β2GPI antibodies contribute to the development of autoimmune-mediated atherosclerosis

Keywords

autoimmune-mediated atherosclerosis β2-glycoprotein I intima-media thickness oxidized low-density lipoprotein systemic lupus erythematosus

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References

Ward MM. Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus . Arthritis Rheum 1999; 42: 338-346 .

Aranow C , Ginzler EM. Epidemiology of cardiovascular disease in systemic lupus erythematosus . Lupus 2000; 9: 166-169 .

Schattner A , Liang MH. The cardiovascular burden of lupus; a complex challenge . Arch Intern Med 2003; 163: 1507-1510 .

Esdaile JM , Abrahamowicz M , Grodzicky T et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus . Arthritis Rheum 2001; 44: 2331-2337 .

Doria A , Shoenfeld Y , Wu R et al. Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus . Ann Rheum Dis 2003; 62: 1071-1077 .

Steinberg D. Atherogenesis in perspective: Hypercholesterolemia and inflammation as partners in crime . Nature Med 2002; 8: 1211-1217 .

Steinberg D , Parthasarathy S , Carew TE , Khoo JC , Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity . N Engl J Med 1989; 320: 915-924 .

Heinecke JW. Mechanisms of oxidative damage of low-density lipoprotein in human atherosclerosis . Curr Opin Lipid 1997; 8: 268-274 .

Shoenfeld Y , Gerli R , Doria A et al. Accelerated atherosclerosis in autoimmune rheumatic diseases . Circulation 2005; 112: 3337-3347 .

10.

Salonen JT , Yla-Herttuala S , Yamamoto R et al. Autoantibodies against oxidized LDL and progression of carotid atherosclerosis . Lancet 1992; 339: 883-887 .

11.

Brey RL , Abbott RD , Curb JD et al. β2-glycoprotein I dependent anti-cardiolipin antibodies and the risk of ischemic stroke and myocardial infarction . Stroke 2001; 32: 1701-1706 .

12.

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 .

13.

George J , Harats D , Gilburd B et al. Immunolocalization of β2-glycoprotein I (apolipoprotein H) to human atherosclerotic plaques: potential implications for lesion progression . Circulation 1999; 99: 2227-2230 .

14.

Yla-Herttuala S , Palinski W , Rosenfeld ME et al. Evidence for presence of oxidatively modified low-density lipoprotein in atherosclerotic lesions of rabbit and man . J Clin Invest 1989; 85: 1086-1095 .

15.

George J , Harats D , Gilburd B et al. Adoptive transfer of β2- glycoprotein I reactive lymphocytes enhances early atherosclerosis in LDL receptor-deficient mice . Circulation 2000; 102: 1822-1827 .

16.

Ames PRJ , Alves J , Murat I , Isenberg DA , Nourooz-Zadeh J. Oxidative stress in systemic lupus erythematosus and allied conditions with vascular involvement . Rheumatology 1999; 38: 529-534 .

17.

Morgan PE , Sturgess AD , Davies M. Increased levels of serum protein oxidation and correlation with disease activity in systemic lupus erythematosus . Arthritis Rheum 2005; 52: 2069-2079 .

18.

Frostegard J , Svenungsson E , Wu R et al. Lipid peroxidation is enhanced in patients with systemic lupus erythematosus and is associated with arterial and renal disease manifestations . Arthritis Rheum 2005; 52: 192-203 .

19.

Delgado Alves J , Ames PR , Donohue S et al. Antibodies to high-density lipoprotein and β2-glycoprotein I are inversely correlated with paraoxonase activity in systemic lupus erythematosus and primary antiphospholipid syndrome . Arthritis Rheum 2002; 46: 2686-2694 .

20.

Hasunuma Y , Matsuura E , Makita Z , Katahira T , Nishi S , Koike T. Involvement of β2-glycoprotein I and anticardiolipin antibodies in oxidatively modified low-density lipoprotein uptake by macrophages . Clin Exp Immunol 1997; 107: 569-573 .

21.

Kobayashi K , Kishi M , Atsumi T et al. Circulating oxidized LDL forms complexes with β2-glycoprotein I: implication as an atherogenic autoantigen . J Lipid Res 2003; 44: 716-726 .

22.

Lopez D , Garcia-Valladares I , Palafox-Sanchez C et al. Oxidized low-density lipoprotein/β2-glycoprotein I complexes and autoantibodies to oxLig-1/β2-glycoprotein I in patients with systemic lupus erythematosus and antiphospholipid syndrome . Am J Clin Pathol 2004; 121: 426-436 .

23.

Lopez D , Kobayashi K , Merrill JT , Matsuura E , Lopez LR. IgG Autoantibodies against β2-glycoprotein I complexed with a lipid ligand derived from oxidized low-density lipoprotein are associated with arterial thrombosis in antiphospholipid syndrome . Clin Dev Immunol 2003; 10: 203-211 .

24.

Kobayashi K , Matsuura E , Liu Q et al. A specific ligand for β2-glycoprotein I mediates autoantibody-dependent uptake of oxidized low density lipoprotein by macrophages . J Lipid Res 2001; 42: 697-709 .

25.

Liu Q , Kobayashi K , Inagaki J et al. -carboxyl variants of 7-ketocholesteryl esters are ligands for β2-glycoprotein I and mediate antibody-dependent uptake of oxidized LDL by macrophages . J Lipid Res 2002; 43: 1486-1495 .

26.

Lopez LR , Simpson DF , Hurley BL , Matsuura E. OxLDL/β2GPI complexes and autoantibodies in patients with systemic lupus erythematosus, systemic sclerosis, and antiphospholipid syndrome: pathogenic implications for vascular involvement . Ann N Y Acad Sci 2005; 1051: 313-322 .

27.

Tan EM , Cohen AS , Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus . Arthritis Rheum 1982; 25: 1271-1277 .

28.

Guzman J , Cardiel MH , Arce-Salinas A , Sanchez-Guerrero J , Alarcon-Segovia D. Measurement of disease activity in systemic lupus erythematosus: prospective validation of 3 clinical indices . J Rheumatol 1992; 19: 1551-1558 .

29.

Manzi S , Selzer F , Sutton-Tyrrell K et al. Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus . Arthritis Rheum 1999; 42: 51-60 .

30.

Roman MJ , Shanker BA , Davis A et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus . N Engl J Med 2003; 349: 2399-2406 .

31.

Vlachoyiannopoulos PG , Kanellopoulos PG , Ioannidis JPA , Tektonidou MG , Mastorakou I , Moutsopoulos HM. Atherosclerosis in premenopausal women with antiphospholipid syndrome and systemic lupus erythematosus: a controlled study . Rheumatology 2003; 42: 645-651 .

32.

Medina G , Casaos D , Jara LJ et al. Increased carotid artery intima-media-thickness may be associated with stroke in primary antiphospholipid syndrome . Ann Rheum Dis 2003; 62: 607-610 .

33.

George J , Blank M , Hojnik M et al. Oxidized low-density lipoprotein (oxLDL) but not LDL aggravates the manifestations of experimental antiphospholipid syndrome (APS) . Clin Exp Immunol 1997; 108: 227-233 .

34.

Shoenfeld Y , Wu R , Dearing LD , Matsuura E.

Are anti-oxidized low-density lipoprotein antibodies pathogenic or protective?

Circulation 2004; 110: 2552-2558 .