Abstract 681: The Effects of a Sustained-Release N-acetylcysteine Prodrug on Vascular Inflammation in Experimental Atherosclerosis
Background: Oxidative stress plays a key role in the development of atherosclerosis. N-acetylcysteine (NAC) has the potential to reduce oxidative stress and inflammation, but has a short half-life and low oral bioavailability. We studied a sustained-release formulation of NAC for the suppression of vascular inflammation in experimental atherosclerosis.
Methods: ApoE-deficient mice (n=17) were started on a high-fat diet at the age of 7-13 weeks and given a daily oral gavage of either sustained-release NAC (n=8, 200mg/kg/mouse, total ~5040mg) or phosphate buffered saline (n=9) for 12 weeks. The sustained-release NAC formulation was an esterified prodrug called SURE-NACTM (Tiara Pharmaceuticals, Inc., Sunnyvale, CA). After 12 weeks, aortae were harvested and histology/immunohistochemistry performed. The levels of inflammatory cytokines in the plasma were evaluated using antibody-conjugated bead sets for 26 mouse cytokines and chemokines in multiplexed sandwich immunoassay format.
Results: Lesion lipid area was significantly reduced in mice treated with sustained-release NAC compared to controls, for both the entire aorta and the aortic root: Lesion lipid area in entire aorta (% of total area) - 6.5±0.8% vs 13.3±1.1%, p<0.001; lesion lipid area in aortic root - 0.08±0.01mm2 vs 0.17±0.02mm2, p<0.001. Immunohistochemistry of the aortic root demonstrated that both macrophages and matrix metalloproteinase (MMP)-2 were also significantly suppressed by sustained-release NAC: Macrophages - 29.4±5.8% vs 55.6±3.2%, p<0.001; MMP-2 - 10.3±2.6% vs 19.2±2.9%, p<0.05. Inflammatory cytokines in mice treated with sustained-release NAC were significantly decreased compared to control (IL-2: 18.2%, IL-5: 47.6%, TNF-α: 34.2%, MIP-1α: 34.5% reduction). The levels of IL-2, IL-5, TNF-α, and MIP-1α showed a significant moderate correlation with both macrophage density and lipid area in the aortic sinus.
Conclusions: A sustained-release NAC prodrug showed substantial suppression of lesion lipid area, macrophage infiltration, and inflammatory cytokines in experimental atherosclerosis. This may provide a novel daily oral therapy to reduce vascular inflammation for the prevention and treatment of atherosclerosis.
Author Disclosures: H. Kosuge: None. Y. Arad: None. T. Saito: None. J.M. Spin: None. M. Isobe: None. M.V. McConnell: Research Grant; Significant; Tiara Pharmaceuticals.
- © 2015 by American Heart Association, Inc.