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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 27, 2006; DOI: 10.1124/jpet.106.109298

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Received for publication June 20, 2006.
Revised September 26, 2006.
Accepted for publication September 26, 2006.

The NO-donating pravastatin derivative (NCX 6550) reduces Splenocyte Adhesion and ROS Generation in Normal and Atherosclerotic Mice

Gary Dever 1, Corinne M Spickett 1, Simon Kennedy 1, Catherine Rush 1, Gail Tennant 1, Angela Monopoli 2, Cherry L Wainwright 3*

1 University of Strathclyde 2 Nicox Research Institute 3 The Robert Gordon University

* Address correspondence to: E-mail: c.wainwright{at}rgu.ac.uk

Abstract

Statins possess anti-inflammatory effects that may contribute to their ability to slow atherogenesis while nitric oxide (NO) also influences inflammatory cell adhesion. This study aimed to determine whether a novel NO-donating pravastatin derivative, NCX 6550, has greater anti-inflammatory properties compared to pravastatin in normal and atherosclerotic ApoE -/- mice. C57Bl/6 and ApoE -/- mice were administered pravastatin (40 mg/kg), NCX 6550 (48.5 mg/kg) or vehicle orally for 5 days. Ex vivo studies assessed splenocyte adhesion to arterial segments and splenocyte ROS generation. NCX 6550 significantly reduced splenocyte adhesion to artery segments in both C57Bl/6 (8.8 ± 1.9 vs 16.6 ± 6.7 % adhesion; P<0.05) and ApoE -/- mice (9.3 ± 2.9 vs 23.4 ± 4.6 % adhesion; P<0.05) concomitant with an inhibition of endothelial ICAM-1 expression. NCX 6550 also significantly reduced PMA-induced ROS production that was enhanced in isolated ApoE -/- splenocytes. Conversely, pravastatin had no significant effects on adhesion in normal or ApoE -/- mice, but reduced the enhanced ROS production from ApoE -/- splenocytes. In separate groups of ApoE -/- mice, NCX 6550 significantly enhanced endothelium-dependent relaxation to carbachol in aortic segments precontracted with phenylephrine (-logEC50 6.37 ± 0.37) compared to both vehicle (-logEC50 5.81 ± 0.15; P<0.001) and pravastatin (-log EC50 5.57 ± 0.45; P<0.05) treated mice. NCX 6550 also significantly reduced plasma MCP-1 levels (648.8 pg/ml) compared to both vehicle (1191.1 pg/ml; P<0.001) and pravastatin (847±71.0 pg/ml; P<0.05) treatment. These data show that NCX 6550 exerts superior anti-inflammatory actions compared to pravastatin, possibly through NO-related mechanisms.


Key words: HMG-CoA reductase, adhesion molecule, atherosclerosis, nitric oxide, reactive oxygen species, statin




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