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Nitric oxide-donating statins: a new concept to boost the lipid-independent effects.

This editorial refers to ‘Nitric oxide enhances the anti-inflammatory and anti-atherogenic activity of atorvastatin in a mouse model of accelerated atherosclerosis’ by S. Momi et al ., doi:10.1093/cvr/cvs100. 

Statins decrease endogenous hepatic cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and augment systemic clearance of cholesterol-rich lipoproteins by the up-regulation of hepatic LDL receptors. Furthermore, this class of drug exerts a variety of so-called pleiotropic beneficial effects on the cardiovascular system. Atherosclerosis is initiated by impaired endothelial function characterized by a reduction in endothelial nitric oxide (NO) bioavailability. LDL-cholesterol (LDL-C) is an important negative regulator of endothelial NO synthase activity. In addition to their lipid-lowering effects, one central biological action of statins is their ability to ameliorate the impaired bioavailability of NO.1 Mechanistically, this occurs through increased expression (by inhibition of geranylgeranylation of small G-proteins)2 or enhanced activation (phosphorylation, activation of phosphatidylinositol 3-kinase and Akt) of endothelial NO synthase (eNOS).3 Consequently, statins improve vasodilation, exert antioxidative effects, and inhibit platelet aggregation, monocyte adhesion, and smooth muscle proliferation—all processes with disturbed regulation in atherosclerosis ( Figure 1 ). On top of—and through—enhancing NO bioavailability, statins have potent anti-inflammatory effects: they decrease inflammation in the vascular wall, in atherosclerotic plaques, and in circulating mononuclear cells and mobilize endothelial progenitor cells from the bone marrow.4 A complete review of vascular effects of statins can be found elsewhere.5 



Figure 1 
Both NO and HMG-CoA reductase inhibitors exert a variety of similar vasoprotective, anti-atherosclerotic functions. The eNOS is the predominant NO-producing enzyme in the vasculature. In the physiological ‘coupled’ state, eNOS forms dimers that are stabilized by the cofactor BH4 to generate more NO …