Combined superoxide dismutase mimetic and peroxynitrite scavenger protects against neointima formation after endarterectomy in association with decreased proliferation and nitro-oxidative stress

K. Hirschberg, T. Radovits, S. Korkmaz, S. Loganathan, S. Zöllner, B. Seidel, S. Páli, E. Barnucz, B. Merkely, M. Karck, G. Szabó

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Abstract

Objective: 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 μmol l-1) and reduced in the treatment group (3.2 ± 2.1 μmol 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.

Original languageEnglish
Pages (from-to)168-175
Number of pages8
JournalEuropean Journal of Vascular and Endovascular Surgery
Volume40
Issue number2
DOIs
Publication statusPublished - Aug 1 2010

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Keywords

  • Antioxidants
  • Carotid arteries
  • Gene expression
  • Peroxynitrite
  • Restenosis

ASJC Scopus subject areas

  • Surgery
  • Cardiology and Cardiovascular Medicine

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