Combined superoxide dismutase mimetic and peroxynitrite scavenger protects against neointima formation after endarterectomy in association with decreased proliferation and nitro-oxidative stress.
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 1h 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 micromol l(-1)) and reduced in the treatment group (3.2+/-2.1 micromol 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.
Hirschberg
K
K
Experimental Laboratory of Cardiac Surgery, University of Heidelberg, Germany. hirschbergkristof@gmail.com
Radovits
T
T
Korkmaz
S
S
Loganathan
S
S
Zöllner
S
S
Seidel
B
B
Páli
S
S
Barnucz
E
E
Merkely
B
B
Karck
M
M
Szabó
G
G
D000818:Animals; D016893:Carotid Stenosis / Q000378:metabolism* / Q000517:prevention & control / Q000601:surgery; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D016894:Endarterectomy, Carotid; D005609:Free Radicals / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006965:Hyperplasia; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D015227:Lipid Peroxidation; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D030421:Peroxynitrous Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051127:Scavenger Receptors, Class E; D055502:Secondary Prevention; D017539:Tunica Intima / Q000473:pathology
D005609:Free Radicals; D008665:Metalloporphyrins; D051127:Scavenger Receptors, Class E; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D030421:Peroxynitrous Acid