Antibodies against electronegative LDL inhibit atherosclerosis in LDLr-/- mice.
In order to determine the effect of antibodies against electronegative low-density lipoprotein LDL(-) on atherogenesis, five groups of LDL low receptor-deficient (LDLr-/-) mice (6 per group) were immunized with the following antibodies (100 microg each): mouse anti-LDL(-) monoclonal IgG2b, rabbit anti-LDL(-) polyclonal IgG or its Fab fragments and mouse irrelevant monoclonal IgG and non-immunized controls. Antibodies were administered intravenously one week before starting the hypercholesterolemic diet (1.25% cholesterol) and then every week for 21 days. The passive immunization with anti-LDL(-) monoclonal IgG2b, polyclonal antibody and its derived Fab significantly reduced the cross-sectional area of atherosclerotic lesions at the aortic root of LDLr-/- mice (28.8 +/- 9.7, 67.3 +/- 17.02, 56.9 +/- 8.02 microm(2) (mean +/- SD), respectively) compared to control (124.9 +/- 13.2 microm(2)). Vascular cell adhesion molecule-1 protein expression, quantified by the KS300 image-analyzing software, on endothelium and the number of macrophages in the intima was also decreased in aortas of mice treated with anti-LDL(-) monoclonal antibody (3.5 +/- 0.70 per field x 10) compared to controls (21.5 +/- 3.5 per field x 10). Furthermore, immunization with the monoclonal antibody decreased the concentration of LDL(-) in blood plasma (immunized: 1.0 +/- 1.4; control: 20.5 +/- 3.5 RLU), the amount of cholesterol oxides in plasma (immunized: 4.7 +/- 2.7; control: 15.0 +/- 2.0 pg COx/mg cholesterol) and liver (immunized: 2.3 +/- 1.5; control: 30.0 +/- 26.0 pg COx/mg cholesterol), and the hepatic content of lipid hydroperoxides (immunized: 0.30 +/- 0.020; control: 0.38 +/- 0.15 ng/mg protein). In conclusion, antibodies against electronegative LDL administered intravenously may play a protective role in atherosclerosis.
Grosso
D M
DM
Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brasil.
Ferderbar
S
S
Wanschel
A C B A
AC
Krieger
M H
MH
Higushi
M L
ML
Abdalla
D S P
DS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D005260:Female; D007116:Immunization, Passive / Q000379:methods*; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage / Q000276:immunology; D007074:Immunoglobulin G / Q000008:administration & dosage* / Q000276:immunology; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000276:immunology; D008077:Lipoproteins, LDL / Q000008:administration & dosage* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011817:Rabbits; D011973:Receptors, LDL / Q000276:immunology* / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D019010:Vascular Cell Adhesion Molecule-1; C019455:low density lipoprotein inhibitor