Combined Superoxide Dismutase Mimetic and Peroxynitrite Scavenger Protects Against Neointima Formation After Endarterectomy in Association with Decreased Proliferation and Nitro-oxidative Stress

Reactive oxygen and nitrogen species (e.g., peroxynitrite) may trigger neointima formation leading to restenosis. In a rat carotid endarterectomy (CEA) model, we investigated the effects of the manganese(III)tetrakis(4-benzoic acid)porphyrin (MnTBAP), a superoxide dismutase (SOD) mimetic and peroxynitrite scavenger on neointima formation. Methods: CEA was performed in male Sprague Dawley rats. Animals received either vehicle (control group; n = 15) or 15 mg kg(-1) day(-1) MnTBAP intraperitoneally for 3 weeks (treatment group; n = 13). Four groups of carotids were analysed: the left, uninjured carotids (sham) and the right, injured carotids (control CEA) from the control group, the right, injured carotids from the treatment group (CEA + MnTBAP) and an additional group of carotids that were harvested 1 h following endarterectomy. The analysis of carotid arteries was performed by histology, immunohistochemistry and real-time polymerase chain reaction (PCR). Plasma malondialdehyde (MDA) levels were measured by lipid hydroperoxidase assay. Results: Stenosis rate (10.5 +/- 8.1% vs. 45.4 +/- 28.3%), the percentage of proliferating cell nuclear antigen-positive cells (13.4 +/- 7.1% vs. 23.3 +/- 11.0%) and nitrotyrosine immunoreactivity (5.8 +/- 1.9 vs. 8.0 +/- 2.0) were significantly reduced in the vascular wall of the CEA + MnTBAP group compared with control CEA group. Ratio of Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL)-positive nuclei was significantly lower after antioxidant therapy (41.7 +/- 26.7% vs. 64.9 +/- 18.5%). Plasma MDA levels increased after endarterectomy (11.7 +/- 4.8 vs. 4.1 +/- 2.0 mu mol l(-1)) and reduced in the treatment group (3.2 +/- 2.1 mu mol l(-1)). No significant gene regulation after MnTBAP treatment could be noted. Conclusions: MnTBAP decreased neointima formation, which was associated with reduced vascular smooth muscle cell proliferation and attenuated local and systemic nitro-oxidative stress. (C) 2010 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.