Annexin A5 Therapy Attenuates Vascular Inflammation and Remodeling and Improves Endothelial Function in Mice

Objective-Annexin A5 (AnxA5) has antithrombotic, antiapoptotic, and antiinflammatory properties; we investigated its effectiveness against vascular inflammation, remodeling, and dysfunction in accelerated atherosclerosis. Methods and Results-AnxA5 (1 mg/kg per day or vehicle) was investigated in vascular injury models in hypercholesterolemic apolipoprotein E (ApoE)3*Leiden mice. AnxA5 treatment reduced adhesion and infiltration of leukocytes by 71% to 69% (P = 0.015, P = 0.031) and macrophages by 51% to 87% (P = 0.014, P = 0.018), as well as monocyte chemotactic protein-1 and tumor necrosis factor-alpha expression in a femoral artery inflammation model (perivascular cuff for 3 days), indicating reduced vascular inflammation. In a vein graft model, 28 days of AnxA5 treatment reduced vein graft thickening (48%; P = 0.006) and leukocyte infiltration (46%; P = 0.003). In these mice, reduced plasma concentrations of IFN-gamma (-72%; P = 0.040), granulocyte colony-stimulating factor (-41%; P = 0.010), and macrophage inflammatory protein-1 beta (MIP-1 beta) (-66%; P = 0.020) were measured, indicating reduced systemic inflammation. An in vitro endothelial cell model shows the importance of AnxA5's anticoagulant properties in reducing vascular inflammation. Endothelium-mediated dilatation in hypercholesterolemic ApoE((-/-)) mice was improved by 3 days of AnxA5 treatment, shown by improved systolic and diastolic blood pressure reductions in response to metacholine, which could be abolished by L-Nitro-Arginine-Methyl Ester (L-NAME), indicating nitric oxide involvement. Conclusion-AnxA5 reduced local vascular and systemic inflammation and vascular remodeling and improved vascular function, indicating that it has a therapeutic potential against atherosclerotic cardiovascular diseases. (Arterioscler Thromb Vasc Biol. 2011;31:95-101.)