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

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·L−1 control) and increased cytotoxic ONOO‐ (299 ± 15 vs. 187 ± 11 nmol·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.