Abstract 17166: First Approach to Stimulate Arteriogenesis Using Monoclonal Antibodies: Blocking the Interferon-alpha/beta Receptor Subunit 1 Stimulates Restoration of Perfusion in a Murine Hindlimb-ischemia Model Without Affecting Atherosclerosis
Purpose: Increased expression of interferon (IFN)-beta was shown in patients with insufficient coronary collaterals. Furthermore, mice treated with IFN-β demonstrate inhibition of collateral artery growth (arteriogenesis). Interestingly, type I interferons (IFN-alpha and IFN-beta) have been identified as proatherosclerotic cytokines and in mouse models of atherosclerosis, IFN-beta treatment accelerated lesion formation and increased accumulation of macrophages in plaques. We hypothesized that arteriogenesis can be stimulated using monoclonal antibodies inhibiting IFN-beta signaling without accelerating atherosclerosis.
Methods: In an atherosclerotic murine hindlimb-ischemia model, LDLR-/- mice were treated during a 4-week period with monoclonal antibodies specific for mouse Interferon-α/β Receptor subunit 1 (IFNAR-1) or murine IgG isotype as control. Hindlimb perfusion was measured using laser Doppler perfusion imaging (LDPI) directly after femoral artery ligation as well as at 2, 7, 14 and 28 days following ligation. We used a disease model to investigate effects of anti-IFNAR-1 on atherosclerosis, which was evaluated with histology to determine plaque area and composition.
Results: Hindlimb perfusion restoration after femoral artery ligation was improved in mice treated with anti-IFNAR-1 compared to controls as assessed by LDPI after 7, 14 and 28 days (treatment vs. control; 7 days: 35.6 ± 16.5% vs. 23.6 ± 8.7%, p=0.027; 14 days: 51.4 ± 17.2% vs. 35.0 ± 12.3%, p 0.010; 28 days 71.5 ± 13.8% vs. 54.0 ± 16.3%, p=0.005). Total plaque area (treatment vs. control: 118.8 ± 46.1x103 μm2 vs. 139.3 ± 46.5 x103 μm2, p=0.275) as well as composition were unaffected.
Conclusion: Blocking IFNAR-1 using monoclonal antibodies stimulates collateral artery growth in mice and has a neutral effect on atherosclerosis.
- © 2013 by American Heart Association, Inc.