Anti-atherogenic effect of statins: role of nitric oxide, peroxynitrite and haem oxygenase-1 (original) (raw)

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 ONOOreleased from isolated aortae by calcium ionophore were measured with nanosensors placed 6 Ϯ 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 Ϯ 3%, decreased NO (230 Ϯ 16 vs. 433 Ϯ 17 nmol•L-1 control) and increased cytotoxic ONOO-(299 Ϯ 15 vs. 187 Ϯ 11 nmol•L-1 control). The concentration ratio of [NO]/[ONOO-] decreased from 2.3 Ϯ 0.1 (normal) to 0.7 Ϯ 0.1 indicating an increase of nitroxidative stress in atherosclerotic endothelium. Expression of HO-1 protein increased by 20 Ϯ 8% in atherosclerosis and further increased (about 30%) after treatment with statins. Statins partially restored the [NO]/[ONOO-] balance (1.5 Ϯ 0.1 for atorvastatin and 1.4 Ϯ 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.