Abstract
Atherosclerosis, the underlying pathology of most cardiovascular diseases, is triggered by the retention of apolipoprotein B (apoB)-containing lipoproteins in the arterial wall through electrostatic interactions with glycosaminoglycan (GAG) side chains of proteoglycans. Previously, we reported the antiatherogenic properties of the chimeric monoclonal antibody (mAb) chP3R99-LALA, which binds sulfated GAGs, inhibits low-density lipoprotein (LDL)–chondroitin sulfate (CS) association, and abrogates LDL oxidation and foam cell formation. In preventive and therapeutic settings, apoE-deficient (apoE−/−) mice immunized with 50 μg of this mAb showed reduced atherosclerotic lesions related with the induction of autologous anti-GAG antibodies. Knowing that age and sex are major non-modifiable risk factors in the development of atherosclerosis, the present study aimed to assess the influence of these variables on the capacity of chP3R99-LALA mAb to generate an anti-CS antibody response. Also, we aimed at defining the impact of the dose of chP3R99-LALA on the anti-CS antibody induction and the atheroprotective effect of this mAb in apoE−/− mice. Neither age nor sex had an impact in the IgG anti-CS antibody response induced by s.c. immunization with this mAb. Moreover, chP3R99-LALA mAb reduced atherosclerotic lesions to a similar extent in both young male and female apoE−/− mice fed a hypercholesterolemic diet and, in middle-aged female apoE−/− mice, with spontaneous lesions. On the other hand, increasing the dose of chP3R99-LALA (200 vs. 50 μg) elicited an anti-idiotype antibody cascade characterized by higher levels of anti-idiotype (Ab2), anti-anti-idiotype (Ab3), and anti-CS antibody responses. Moreover, this dose increment resulted in a striking reduction of aortic atherosclerotic lesions in immunized mice.
Highlights
Cardiovascular diseases (CVDs) still prevail as the leading cause of death worldwide [1]
The specificity of the purified antibodies was confirmed by enzyme-linked immunoadsorbent assay (ELISA) and protein concentration was estimated by optical density (OD) at 280 nm
Antibody responses could be reduced in magnitude and the antibodies could be less protective compared with those induced in young adults [34,35,36,37,38,39,40]
Summary
Cardiovascular diseases (CVDs) still prevail as the leading cause of death worldwide [1]. Atherosclerosis, the underlying pathology in most CVD, is initiated by the subendothelial retention of apoB-containing lipoproteins [3,4,5]. Idiotypic Cascade Induced by an Anti-GAG mAb. Idiotypic Cascade Induced by an Anti-GAG mAb This retention occurs by electrostatic interactions between glycosaminoglycan (GAG) chains and basic residues present in apoB-containing lipoproteins [6, 7]. Epidemiological studies have demonstrated that different risk factors, including hypercholesterolemia, hypertension, diabetes, smoking, age, and gender influence the development and progression of atherosclerosis [14,15,16,17]. Aging increases atherosclerosis in both male and female mice, the influence of gender in the extent of the disease remains controversial [21,22,23,24]
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