Anti-atherogenic effect of statins: role of nitric oxide, peroxynitrite and haem oxygenase-1.
OBJECTIVE
The pleiotropic effects of HMG-CoA inhibitors (statins), which include anti-inflammation, antioxidation and immunomodulation, are not yet fully understood. The present study was designed to elucidate the role of nitric oxide (NO), peroxynitrite (ONOO(-)) and haem oxygenase-1 (HO-1) in the anti-atherogenic effect of statins.


METHODS
Normal and atherosclerotic New Zealand rabbits were treated with atorvastatin or simvastatin in the presence or absence of inhibitors and promoters of endothelial nitric oxide synthase (eNOS) and HO-1. NO and ONOO(-) released from isolated aortae by calcium ionophore were measured with nanosensors placed 6 +/- 2 nm from aortic endothelium. Expression of eNOS and HO-1 protein, HO activity, plasma malondialdehyde (MDA) and vessel wall thickness were also measured.


RESULTS
Hypercholesterolaemia decreased eNOS expression by 31 +/- 3%, decreased NO (230 +/- 16 vs. 433 +/- 17 nmol x L(-1) control) and increased cytotoxic ONOO(-) (299 +/- 15 vs. 187 +/- 11 nmol x L(-1) control). The concentration ratio of [NO]/[ONOO(-)] decreased from 2.3 +/- 0.1 (normal) to 0.7 +/- 0.1 indicating an increase of nitroxidative stress in atherosclerotic endothelium. Expression of HO-1 protein increased by 20 +/- 8% in atherosclerosis and further increased (about 30%) after treatment with statins. Statins partially restored the [NO]/[ONOO(-)] balance (1.5 +/- 0.1 for atorvastatin and 1.4 +/- 0.1 simvastatin), decreased MDA and wall thickening. Promoters of eNOS and HO-1 (L-arginine and haemin) ameliorated the [NO]/[ONOO(-)] ratio while their inhibitors (L-NAME or tin-protoporphyrin) showed no improvement in these ratio.


CONCLUSIONS
Atherosclerosis induced an endothelial [NO]/[ONOO(-)] balance indicative of endothelial dysfunction. Statins showed anti-atherosclerotic effects mediated by HO-1/eNOS, restoring the [NO]/[ONOO(-)] imbalance and reducing lipid peroxidation.
Heeba
G
G
Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701-2979, USA.
Moselhy
M E
ME
Hassan
M
M
Khalifa
M
M
Gryglewski
R
R
Malinski
T
T
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001120:Arginine / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000069059:Atorvastatin; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006427:Hemin / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D011524:Protoporphyrins / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D011817:Rabbits; D019821:Simvastatin / Q000494:pharmacology*; D013997:Time Factors
D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008665:Metalloporphyrins; D011524:Protoporphyrins; D011758:Pyrroles; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D008315:Malondialdehyde; D006427:Hemin; D001120:Arginine; D000069059:Atorvastatin; D019821:Simvastatin; C032628:tin protoporphyrin IX; D052250:Nitric Oxide Synthase Type III; D051547:Heme Oxygenase-1; D019331:NG-Nitroarginine Methyl Ester