Abstract 11919: Igg1 Phosphorylcholine Diminishes Murine Atherosclerosis and Ameliorates Plaque Stability via Reduced Intraplaque Angiogenesis and Hemorrhage

Abstract

Introduction: Phosphorylcholine (PC), one of the main oxLDL epitopes, is an important pro-inflammatory damage associated molecular pattern. Epidemiologic data show that natural anti-PC IgM protect against cardiovascular disease. Within atherosclerotic lesions, inflammation and angiogenesis are linked via VEGFA secreting CD163 + macrophages. PC antibodies are recognized for their anti-inflammatory properties, the effect of PC antibodies on intraplaque angiogenesis (IPA) and intraplaque hemorrhage (IPH) is yet unknown. Hypothesis: Newly developed IgG1 PC antibody (PCmAb) inhibits lesion development via IPA and IPH reduction in murine vein graft atherosclerosis. Methods: Hypercholesterolemic male ApoE3*Leiden mice received a (donor) caval vein interposition in the carotid artery and weekly ip injections of (5mg/kg) PCmAb (n=11) or vehicle (n=12) until sacrifice at day 28. Vein graft morphometry and lesion composition including IPA and IPH were evaluated via immunohistochemistry. In vitro PCmAb effects were investigated in Hemoglobin (Hb):Haptoglobin(Hp)-cultured THP-1 macrophages and HUVECs. Results: PCmAb significantly decreased vein graft media area (13%), intima lesion (25%), and increased lumen area with 53% compared to vehicle. PCmAb improved lesion stability by increasing collagen content (18%) and decreased macrophages presence (31%). VCAM-1 and ICAM-1 expression in the vessel wall were also reduced (29%, 36%). PCmAb resulted in 23% decreased CD163 + macrophages content in vein grafts whereas CD163 expression was reduced in Hb:Hp stimulated macrophages. PCmAb significantly reduced neovessel density (34%) and significant reduced EC proliferation and migration with and without oxLDL stimulation. Moreover, PCmAb enhanced maturation of intraplaque angiogenic vessels by increasing neovessel pericyte coverage in vivo (31%). Together, this resulted in a 62%reduction of IPH. Conclusions: PCmAb effectively inhibits murine atherosclerotic lesion formation. PCmAb reduces IPA and IPH by decreased neovessel density and macrophages influx via reduced expression of VCAM-1 and ICAM-1, and increased neovessel maturation in vein graft atherosclerosis. PCmAb holds promise as a new therapeutic approach for plaque stability.