Center of Molecular Immunology, University of Havana, 216 St and 15th Ave, PO Box 16040, Atabey, Playa, Havana 11600, Cuba.
Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):595-604. doi: 10.1161/ATVBAHA.111.238659. Epub 2012 Jan 19.
Subendothelial retention of proatherogenic lipoproteins by proteoglycans is critical in atherosclerosis. The aim of this study was to characterize the recognition and antiatherogenic properties of a chimeric monoclonal antibody (mAb) that reacts with sulfated molecules.
chP3R99 mAb recognized sulfated glycosaminoglycans, mainly chondroitin sulfate (CS), by ELISA. This mAb blocked ≈70% of low-density lipoprotein (LDL)-CS association and ≈80% of LDL oxidation in vitro, and when intravenously injected to Sprague-Dawley rats (n=6, 1 mg/animal), it inhibited LDL (4 mg/kg intraperitoneally, 1 hour later) retention and oxidation in the artery wall. Moreover, subcutaneous immunization of New Zealand White rabbits (n=19) with chP3R99 mAb (100 μg, 3 doses at weekly intervals) prevented Lipofundin-induced atherosclerosis (2 mL/kg, 8 days) with a 22-fold reduction in the intima-media ratio (P<0.01). Histopathologic and ultrastructural studies showed no intimal alterations or slight thickening, with preserved junctions between endothelial cells and scarce collagen fibers and glycosaminoglycans. In addition, immunization with chP3R99 mAb suppressed macrophage infiltration in aorta and preserved redox status. The atheroprotective effect was associated with the induction of anti-CS antibodies in chP3R99-immunized rabbits, capable of blocking CS-LDL binding and LDL oxidation.
These results support the use of anti-sulfated glycosaminoglycan antibody-based immunotherapy as a potential tool to prevent atherosclerosis.
蛋白聚糖对前粥样硬化脂蛋白的亚内皮保留在动脉粥样硬化中至关重要。本研究的目的是描述一种与硫酸化分子反应的嵌合单克隆抗体（mAb）的识别和抗动脉粥样硬化特性。
chP3R99 mAb 通过 ELISA 识别硫酸化糖胺聚糖，主要是硫酸软骨素（CS）。该 mAb 可阻止约 70%的 LDL-CS 结合和约 80%的 LDL 体外氧化，当静脉注射到 Sprague-Dawley 大鼠（n=6，1mg/动物）中时，它抑制 LDL（4mg/kg 腹腔内，1 小时后）在动脉壁中的保留和氧化。此外，用 chP3R99 mAb（100μg，每周间隔 3 次，皮下免疫新西兰白兔（n=19））可预防 Lipofundin 诱导的动脉粥样硬化（2mL/kg，8 天），内膜中层比降低 22 倍（P<0.01）。组织病理学和超微结构研究显示，内膜无改变或轻微增厚，内皮细胞之间的连接保持完好，胶原纤维和糖胺聚糖稀少。此外，用 chP3R99 mAb 免疫抑制主动脉中巨噬细胞浸润，并维持氧化还原状态。这种抗动脉粥样硬化作用与 chP3R99 免疫兔中诱导抗 CS 抗体有关，该抗体能够阻断 CS-LDL 结合和 LDL 氧化。
这些结果支持使用基于抗硫酸化糖胺聚糖抗体的免疫疗法作为预防动脉粥样硬化的潜在工具。
