OC 18.5 - APAC Treatment Limits Collar-induced Carotid Atherosclerotic Plaque Development in ApoE-/- Mice

Background: Mimics of mast cell-derived heparin proteoglycans can be tailored to molecules carrying both antiplatelet (AP) and anticoagulant (AC) properties. These dual APAC constructs can also shield adhesion molecules, i.e., von Willebrand factor, P-selectin and VCAM-1 expressed by endothelial cells upon atherosclerosis development. We hypothesize that via vascular targeting, APAC prevents macrophage accumulation and lesion development.

Aims: Our aim was to determine the efficacy of APAC in inhibiting atherosclerosis in apoE-/- mice.

Methods: Male western-type diet fed apoE-/- mice were equipped with perivascular carotid artery collars (diameter 0.5 mm and length 2 mm) to induce atherosclerosis. This collar triggers various effects on shear forces along the artery. In this model, mRNA expression of adhesion molecules, i.e., ICAM-1, VCAM-1, P-Selectin and Platelet Factor 4 (PF4) are upregulated upon lesion development (all P< 0.05 at 2 weeks after collar placement versus control arteries). Mice were treated with 0.2 mg/kg APAC or vehicle control (i.v, 3x weekly, n=12-14 per group) for 2.5 weeks either at lesion initiation or 2.5 weeks afterwards. At 5 weeks after collar placement, mice were sacrificed. Data are mean ±SEM.

Results: APAC treatment did not affect body weight or plasma total cholesterol levels of the mice during the experiments. Interestingly, when APAC treatment was started from the lesion initiation carotid artery plaque size was reduced by over 50% (APAC: 50±10*10^3 versus controls: 102±13*10^3 µm2; P< 0.01). This observation was aligned with reduced plaque macrophage area (APAC: 20±5*10^3 versus controls: 33±5*10^3 µm2) and collagen content (APAC: 13±4*10^3 versus controls: 28±6*10^3 µm2; P< 0.05). When APAC treatment was started at 2.5 weeks after the lesion initiation, APAC decreased necrosis (P < 0.05) and propagation of atherosclerotic lesions.

Conclusion(s): We report that APAC effectively inhibits atherosclerotic lesion development when administered to apoE-/- mice. APAC may have potential as therapeutic agent to prevent or attenuate atherosclerosis.