Myeloperoxidase-Dependent LDL Modifications in Bloodstream Are Mainly Predicted by Angiotensin II, Adiponectin, and Myeloperoxidase Activity: A Cross-Sectional Study in Men

The present paradigm of atherogenesis proposes that low density lipoproteins (LDLs) are trapped in subendothelial space of the vascular wall where they are oxidized. Previously, we showed that oxidation is not restricted to the subendothelial location. Myeloperoxidase (MPO), an enzyme secreted by neutrophils and macrophages, can modify LDL (Mox-LDL) at the surface of endothelial cells. In addition we observed that the activation of the endothelial cells by angiotensin II amplifies this process. We suggested that induction of the NADPH oxidase complex was a major step in the oxidative process. Based on these data, we asked whether there was an independent association, in 121 patients, between NADPH oxidase modulators, such as angiotensin II, adiponectin, and levels of circulating Mox-LDL. Our observations suggest that the combination of blood angiotensin II, MPO activity, and adiponectin explains, at least partially, serum Mox-LDL levels. 1. Introduction Atherosclerosis is an inflammatory disease involving a crosstalk between vascular cells, monocytes, proinflammatory cytokines, chemokines, and growth factors [1–3]. The current paradigm of early atherosclerosis claims that low-density lipoprotein (LDL) particles are trapped in the subendothelial space of the vascular wall where they can be oxidized. The precise physiological process for LDL oxidation in vivo is still largely unknown and the occurrence of LDL oxidation outside the lesion sites has not definitively been ruled out yet. Evidence accumulated during the last decade has suggested implication of myeloperoxidase (MPO) in inflammation leading to atherogenesis. MPO is produced by macrophages and neutrophils [4] and via its chlorination activity, MPO produces hypochlorous acid (HOCl) from hydrogen peroxide (H2O2) and chloride anion (Cl？). HOCl can oxidize protein-bound amino acid residues among which the formation of 3-chlorotyrosine is considered as specific of the activity of MPO as the latter is the only human enzyme able to produce HOCl. In the context of atherogenesis, MPO, 3-chlorotyrosine, and MPO-dependent modified LDL (Mox-LDL) have all been detected in human atherosclerotic lesions and in the bloodstream [5–8]. We previously demonstrated that Mox-LDL generation could occur in vitro at the surface of the endothelial cells suggesting that it was not restricted to the subendothelial space in vivo [9]. The triad made up by endothelial cell, circulating LDL and MPO, allowed a synergic mechanism for producing Mox-LDL. The starting point of this reaction is the generation of superoxide anion ( )