Monoclonal Antibody chP3R99 Reduces Subendothelial Retention of Atherogenic Lipoproteins in Insulin-Resistant Rats: Acute Treatment Versus Long-Term Protection as an Idiotypic Vaccine for Atherosclerosis.

Autor: Soto Y; Department of Immunobiology Direction of Immunology and Immunotherapy Centre for Molecular Immunology Havana Cuba.; Metabolic and Cardiovascular Disease Laboratory Group on Molecular and Cell Biology of Lipids Alberta Diabetes and Mazankowski Heart Institutes University of Alberta Edmonton AB Canada., Hernández A; Department of Immunobiology Direction of Immunology and Immunotherapy Centre for Molecular Immunology Havana Cuba., Sarduy R; Department of Immunobiology Direction of Immunology and Immunotherapy Centre for Molecular Immunology Havana Cuba., Brito V; Department of Immunobiology Direction of Immunology and Immunotherapy Centre for Molecular Immunology Havana Cuba., Marleau S; Faculté de Pharmacie Université de Montréal Montréal QC Canada., Vine DF; Metabolic and Cardiovascular Disease Laboratory Group on Molecular and Cell Biology of Lipids Alberta Diabetes and Mazankowski Heart Institutes University of Alberta Edmonton AB Canada., Vázquez AM; Innovation and Managing Direction Center for Molecular Immunology Havana Cuba., Proctor SD; Metabolic and Cardiovascular Disease Laboratory Group on Molecular and Cell Biology of Lipids Alberta Diabetes and Mazankowski Heart Institutes University of Alberta Edmonton AB Canada.
Jazyk: angličtina
Zdroj: Journal of the American Heart Association [J Am Heart Assoc] 2024 Jul 02; Vol. 13 (13), pp. e032419. Date of Electronic Publication: 2024 Jun 27.
DOI: 10.1161/JAHA.123.032419
Abstrakt: Background: Atherosclerosis is triggered by the retention of apolipoprotein B-containing lipoproteins by proteoglycans. In addition to low-density lipoprotein, remnant lipoproteins have emerged as pivotal contributors to this pathology, particularly in the context of insulin resistance and diabetes. We have previously reported antiatherogenic properties of a monoclonal antibody (chP3R99) that recognizes sulfated glycosaminoglycans on arterial proteoglycans.
Methods and Results: Solid-phase assays demonstrated that chP3R99 effectively blocked >50% lipoprotein binding to chondroitin sulfate and vascular extracellular matrix in vitro. The preperfusion of chP3R99 (competitive effect) resulted in specific antibody-arterial accumulation and reduced fluorescent lipoprotein retention by ~60% in insulin resistant JCR:LA- cp rats. This competitive reduction was dose dependent (25-250 μg/mL), effectively decreasing deposition of cholesterol associated with lipoproteins. In a 5-week vaccination study in insulin resistant rats with (200 μg subcutaneously, once a week), chP3R99 reduced arterial lipoprotein retention, and was associated with the production of antichondroitin sulfate antibodies (Ab3) able to accumulate in the arteries (dot-blot). Neither the intravenous inoculation of chP3R99 (4.5 mg/kg), nor the immunization with this antibody displayed adverse effects on lipid or glucose metabolism, insulin resistance, liver function, blood cell indices, or inflammation pathways in JCR:LA -cp rats.
Conclusions: Both acute (passive) and long-term administration (idiotypic cascade) of chP3R99 antibody reduced low-density lipoprotein and remnant lipoprotein interaction with proteoglycans in an insulin-resistant setting. These findings support the innovative approach of targeting proatherogenic lipoprotein retention by chP3R99 as a passive therapy or as an idiotypic vaccine for atherosclerosis.
Databáze: MEDLINE
Externí odkaz: