The pro-inflammatory effect of uraemia overrules the anti-atherogenic potential of immunization with oxidized LDL in apoE-/- mice.
BACKGROUND
Uraemia increases oxidative stress, plasma titres of antibodies recognizing oxidized low-density lipoprotein (oxLDL) and development of atherosclerosis. Immunization with oxLDL prevents classical, non-uraemic atherosclerosis. We have investigated whether immunization with oxLDL might also prevent uraemia-induced atherosclerosis in apolipoprotein E knockout (apoE-/-) mice.


METHODS
ApoE-/- mice were immunized with either native LDL (n = 25), Cu(2+)-oxidized LDL (n = 25), PBS (n = 25), the apolipoprotein B-derived peptide P45 (apoB-peptide P45) conjugated to bovine serum albumin (BSA) (n = 25) or BSA (n = 25) prior to induction of uraemia by 5/6 nephrectomy (NX).


RESULTS
Immunization with oxLDL increased plasma titres of immunoglobulin G (IgG) recognizing Cu(2+)-oxLDL and malondialdehyde-modified LDL (MDA-LDL). However, 5/6 NX induced a marked increase in plasma concentrations of anti-oxLDL antibodies as well as pro-atherogenic cytokines [interleukin (IL)-2 (IL-2), IL-4, IL-6 and IL-12)] in native mouse LDL (nLDL)-, oxLDL- and PBS-immunized mice. Even though nLDL- and oxLDL-immunized mice displayed higher anti-MDA-LDL IgG titres than the PBS group, aortic atherosclerosis lesion size was not affected by immunization. Immunization with the apoB-peptide P45, which consistently reduces classical atherosclerosis in non-uraemic mice, also did not reduce lesion size in uraemic apoE-/- mice.


CONCLUSIONS
The results suggest that the pro-inflammatory and pro-atherogenic effect of uraemia overrules the anti-atherogenic potential of oxLDL immunization in apoE-/- mice.
Pedersen
Tanja X
TX
Department of Clinical Biochemistry, KB3011, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark. Tanjax@sund.ku.dk
Binder
Christoph J
CJ
Fredrikson
Gunilla N
GN
Nilsson
Jan
J
Bro
Susanne
S
Nielsen
Lars B
LB
D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D007114:Immunization / Q000379:methods*; D007074:Immunoglobulin G / Q000097:blood; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000276:immunology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014511:Uremia / Q000276:immunology / Q000378:metabolism*
C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D016207:Cytokines; D007074:Immunoglobulin G; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein