Abstract 14013: E-selectin-targeted Novel Nano Polymers Stabilize Atherosclerotic Plaque and Improve Cardiac Remodeling

Abstract

Introduction: Inflammation is implicated in the initiation and progression of cardiovascular disease. Endothelial activation with up-regulation of E-selectin adhesion molecules stimulates leukocyte infiltration leading to atherosclerotic plaque growth, plaque vulnerability and acute myocardial infarction. Hypothesis: Novel E-selectin-targeted polymers, with or without dexamethasone, can prevent plaque progression and adverse cardiac remodeling in atherosclerosis prone ApoE deficient ApoE (-/-) mice. Methods and Results: To target and modulate cardiovascular inflammation we used novel N-(2-hydroxypropyl)-meth-acrylamide polymers conjugated with peptides that bind E-selectin with high affinity, with and without dexamethasone 1mg/kg (P-ESBP-Dex, P-ESBP). Five-month-old ApoE (-/-) mice were fed a high-fat diet (HFD) for 8 weeks. Plaque growth was assessed by vascular ultrasound (US) 4 and 8 weeks after onset of HFD. We used a novel software application designed to measure in-vivo vessel wall anatomy and motion in small-animal models. Following the baseline vascular US, mice were randomized to 4 treatment groups: P-ESBP-Dex, P-ESBP, free dexamethasone or saline, delivered by 4 weekly intraperitoneal injections. Left ventricular remodeling and function were assessed by echocardiography in parallel to the vascular US. We found that both P-ESBP and P-ESBP-Dex selectively targeted atherosclerotic lesions, and reduced wall thickness of the ascending aorta. Furthermore, compared with saline controls, P-ESBP significantly decreased the area of necrotic core in the aortic plaques (74.2±5.9 mm2 vs. 34.7±15.5 mm2, p<0.05). Notably, the addition of dexamethasone to P-ESBP did not improve their therapeutic effect. Finally, P-ESBP attenuated left ventricular diastolic and systolic dilatation, compared with controls. Conclusion: E-selectin binding polymers reduce the growth of atherosclerotic lesions, contribute to plaque stability and prevent adverse cardiac remodeling in ApoE (-/-) mice. We suggest a novel nanomedicine-based therapy for atherosclerosis, unstable plaque, and to prevent adverse cardiac remodeling.