Format

Send to

Choose Destination
See comment in PubMed Commons below
Br J Pharmacol. 2009 Apr;156(8):1256-66. doi: 10.1111/j.1476-5381.2009.00125.x. Epub 2009 Feb 18.

Anti-atherogenic effect of statins: role of nitric oxide, peroxynitrite and haem oxygenase-1.

Author information

1
Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701-2979, USA.

Abstract

BACKGROUND AND PURPOSE:

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.

EXPERIMENTAL APPROACH:

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.

KEY 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 AND IMPLICATIONS:

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.

PMID:
19226281
PMCID:
PMC2697732
DOI:
10.1111/j.1476-5381.2009.00125.x
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Wiley Icon for PubMed Central
    Loading ...
    Support Center