See related article, pages 923–932 In a remarkable article published in this issue of Circulation Research , Ryoo et al1 propose endothelial arginase II as a novel target for the treatment of atherosclerosis. Actually, they already had done so 2 years ago, based on work mainly on cultured human aortic endothelial cells,2 which indeed appeared to provide an unexpected way to explain endothelial dysfunction in terms of NO production.3 This new road to endothelial dysfunction proposed that oxidized low-density lipoproteins (LDLs), which we all agree are a main culprit in the initiation of the atherosclerotic process, increase the activity of arginase II, which, in turn, decreases NO production presumably by shunting the common substrate arginine away from endothelial NO synthase (eNOS) (Figure). Figure. Model of endothelial dysfunction in the hypercholesterolemic mouse as proposed by Ryoo and colleagues.1,2 Left, In the normal mouse aortic endothelium, l-arginine (L-Arg) is transformed by eNOS to NO, which exerts its well-documented beneficial effects (most are not shown for the sake of clarity), including inhibition of the oxidation of LDLs to OxLDL. The byproduct of the reaction, l-citrulline (L-Cit), inhibits arginase II (AaII), which is constrained to the microtubules (MT). Right, In the aortic endothelium of the ApoE−/− and the wild-type hypercholesterolemic mice, the accumulation of OxLDL dislocates arginase II from the microtubules and augments its activity. Arginase II competes with endothelial NO synthase for the common substrate l-arginine, leading to uncoupling of NO synthase and the production of superoxide anions (O![Graphic][1] ,2]), which further enhance the production of OxLDL. The latter also facilitates dissociation of eNOS from the caveolae and reduces the genomic expression of the enzyme, leading to further reduction of the production of NO. This model does not account for the biological effects, if … [1]: F1/embed/inline-graphic-1.gif