Abstract 637: Intervention With Anti-Inflammatory Resolvin E1 Attenuates Atherosclerosis Without Decreasing Plasma Cholesterol and Adds to the Antiatherogenic Effect of Atorvastatin

Abstract

Objective: Atherosclerosis is a multifactorial disease that correlates positively and significantly with low-density lipoprotein (LDL) plasma cholesterol and requires inflammatory components. Whereas reduction of plasma LDL cholesterol is effectively achieved by statins, quenching of the inflammatory factors has not been addressed adequately by existing therapies. Resolvins are naturally-occurring, small molecule lipid mediators with the potential to treat multiple inflammatory diseases. Here we investigated the potency of ω-3 fatty acid eicosapentaenoic acid derived resolvin E1 (RvE1) in attenuating atherosclerosis in APOE*3Leiden transgenic mice. Methods: Mice were fed a hypercholesterolemic diet (0.4%) for nine weeks. Subsequently, mice were randomized and treated with low (1 mg/kg/day) and high (5 mg/kg/day) doses of RvE1, atorvastatin (1.5 mg/kg/day), and the combination of atorvastatin and low dose RvE1 for the following 16 weeks to evaluate the anti-atherogenic effects. Results: Both low and high dose RvE1 treatment significantly (35% and 37%, respectively; p<0.05) attenuated atherosclerotic lesion size, without affecting plasma cholesterol. Plasma cholesterol lowering (24%; p<0.01) atorvastatin reduced the lesion size to a similar extent (27%; p<0.05). Neither RvE1 nor atorvastatin reduced circulating SAA levels. Notably, refined analysis revealed the presence of less severe lesions with RvE1 versus atorvastatin treatment. Importantly, in combination with atorvastatin, RvE1 added to the anti-atherosclerotic effect of atorvastatin, resulting in decreased lesion area (31%), lesion severity (58%) and increased percentage of lesion-free segments (62%). Furthermore, micro-array analysis of aortas from RvE1-treated mice revealed changes in gene expression profiles that are enriched in biological processes involved in stress, defense and immune responses, cell adhesion and superoxide metabolism. Conclusion: RvE1 attenuates atherosclerosis lesion size and lesion severity without lowering plasma cholesterol and SAA levels. Combined RvE1 and atorvastatin treatment was more effective than each compound alone, indicating the potential of RvE1 to be used on top of atorvastatin treatment.