title: Arresting progressive atherosclerosis by immunization with an anti-glycosaminoglycan monoclonal antibody in apolipoprotein E-deficient mice.
abstract: Atherogenesis is associated with the early retention of low-density lipoproteins (LDL) in the arterial intima by interaction with glycosaminoglycan (GAG)-side chains of proteoglycans. Retained LDL undergo reactive oxygen species-mediated oxidation. Oxidized LDL trigger oxidative stress (OS) and inflammation, contributing to atherosclerosis development. Recently, we reported the preventive anti-atherogenic properties of the chimeric mouse/human monoclonal antibody (mAb) chP3R99-LALA, which were related to the induction of anti-chondroitin sulfate antibody response able to inhibit chondroitin sulfate dependent LDL-enhanced oxidation. In the present work, we aimed at further investigating the impact of chP3R99-LALA mAb vaccination on progressive atherosclerosis in apolipoprotein E-deficient mice (apoE(-/-)) fed with a high-fat high-cholesterol diet receiving 5 doses (50 µg) of the antibody subcutaneously, when ~5% of the aortic area was covered by lesions. Therapeutic immunization with chP3R99-LALA mAb halted atherosclerotic lesions progression. In addition, aortic OS was modulated, as shown by a significant (p<0.05) reduction of lipid and protein oxidation, preservation of antioxidant enzymes activity and reduced glutathione, together with a decrease of nitric oxide levels. chP3R99-LALA mAb immunization also regulated aortic NF-κB activation, diminishing the proinflammatory IL1-β and TNF-α gene expression as well as the infiltration of macrophages into the arterial wall. The therapeutic immunization of apoE(-/-) with progressive atheromas and persistent hypercholesterolemia using chP3R99-LALA mAb arrested further development of lesions, accompanied by a decrease of aortic OS and NF-κB-regulated pro-inflammatory cytokine gene expression. These results contribute to broaden the potential use of this anti-GAG antibody-based immunotherapy as a novel approach to target atherosclerosis at different phases of progression.
authors.affiliation: Department of Pharmacology, Center of Marine Bioproducts, Havana 10600, Cuba.
authors.forename: Livan
authors.initials: L
authors.lastname: Delgado-Roche
authors.affiliation: Division of Immunobiology, Center of Molecular Immunology, Havana 11600, Cuba.
authors.forename: Víctor
authors.initials: V
authors.lastname: Brito
authors.affiliation: Center of Advanced Studies of Cuba, La Lisa, Havana 13600, Cuba.
authors.forename: Emilio
authors.initials: E
authors.lastname: Acosta
authors.affiliation: Division of Immunobiology, Center of Molecular Immunology, Havana 11600, Cuba.
authors.forename: Arlenis
authors.initials: A
authors.lastname: Pérez
authors.affiliation: Department of Genomic, Center for Genetic Engineering and Biotechnology, Havana 11600, Cuba.
authors.forename: Julio R
authors.initials: JR
authors.lastname: Fernández
authors.affiliation: Department of Pharmacology and Toxicology, Pharmacy and Food Sciences Institute, University of Havana, Havana 13600, Cuba.
authors.forename: Yanet
authors.initials: Y
authors.lastname: Hernández-Matos
authors.affiliation: Division of Immunobiology, Center of Molecular Immunology, Havana 11600, Cuba.
authors.forename: Tania
authors.initials: T
authors.lastname: Griñán
authors.affiliation: Division of Immunobiology, Center of Molecular Immunology, Havana 11600, Cuba.
authors.forename: Yosdel
authors.initials: Y
authors.lastname: Soto
authors.affiliation: Department of Pharmacology and Toxicology, Pharmacy and Food Sciences Institute, University of Havana, Havana 13600, Cuba.
authors.forename: Olga S
authors.initials: OS
authors.lastname: León
authors.affiliation: Faculty de of Pharmacy Université de Montréal, Montréal, Québec, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Marleau
authors.affiliation: Innovation Managing Direction, Center of Molecular Immunology, Havana 11600, Cuba. Electronic address: maruchi@cim.sld.cu.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Vázquez
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000473:pathology*; D002809:Chondroitin Sulfates / Q000037:antagonists & inhibitors* / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006025:Glycosaminoglycans / Q000037:antagonists & inhibitors* / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D016133:Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014611:Vaccination / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D006025:Glycosaminoglycans; D011993:Recombinant Fusion Proteins; D002809:Chondroitin Sulfates
keywords: Atherosclerosis; Glycosaminoglycans; Immunotherapy; Inflammation; Monoclonal antibody; Oxidative stress