Low-density lipoprotein modified by myeloperoxidase in inflammatory pathways and clinical studies

Abstract

Oxidation of low-density lipoprotein (LDL) has a key role in atherogenesis. Among the different models of oxidation that have been studied, the one using myeloperoxidase (MPO) is thought to be more physiopathologically relevant. Apolipoprotein B-100 is the unique protein of LDL and is the major target of MPO. Furthermore, MPO rapidly adsorbs at the surface of LDL, promoting oxidation of amino acid residues and formation of oxidized lipoproteins that are commonly named Mox-LDL. The latter is not recognized by the LDL receptor and is accumulated by macrophages. In the context of atherogenesis, Mox-LDL accumulates in macrophages leading to foam cell formation. Furthermore, Mox-LDL seems to have specific effects and triggers inflammation. Indeed, those oxidized lipoproteins activate endothelial cells and monocytes/macrophages and induce proinflammatory molecules such as TNF α and IL-8. Mox-LDL may also inhibit fibrinolysis mediated via endothelial cells and consecutively increase the risk of thrombus formation. Finally, Mox-LDL has been involved in the physiopathology of several diseases linked to atherosclerosis such as kidney failure and consequent hemodialysis therapy, erectile dysfunction, and sleep restriction. All these issues show that the investigations of MPO-dependent LDL oxidation are of importance to better understand the inflammatory context of atherosclerosis.

Figure 1

Scheme of the interconversion between different oxidized states of myeloperoxidase. The first reaction is the oxidation of native MPO to Compound I by a two-electron reaction. In the halogenation cycle, Compound I is backconverted to native MPO, and a two-electron oxidation of (pseudo-) halide generates hypo- (pseudo-) halogenous acid. In the peroxidase cycle, Compound I can oxidize an electron donor via 1-electron process transforming Compound I to Compound II and the electron donor to a radical product. Compound II can be reduced to native MPO by using 1 electron from other electron donors.

Figure 2

Role of myeloperoxidase and Mox-LDL in triggering inflammation and atherosclerosis plaque formation. Activation of neutrophils and monocytes leads to MPO release in the extracellular space, that is, the circulation. Due to its cationic properties, free MPO rapidly adsorbs at the surface of endothelial cells or native LDL (Nat-LDL). Angiotensin II (AT II) activates endothelial cells via angiotensin receptor 1 (AT-R1), which in turn produces superoxide anion (O₂ ^•−) via the NADPH oxidase complex, (NOX2). O₂ ^•− is rapidly transformed into hydrogen peroxide (H₂O₂) spontaneously or by the enzyme superoxide dismutase (SOD). Nat-LDL can be so directly oxidized by MPO/H₂O₂/chloride system in the circulation and form the so-called Mox-LDL. The latter can in turn pass through the endothelium (due to endothelial dysfunction) to the subendothelial space where it will be recognized by macrophages and eliminated. Accumulation of oxidized lipoproteins leads to foam cell formation and lipid accumulation in the subendothelial space. Nat-LDL, can also directly pass through the endothelial wall where they are oxidized by MPO in the subendothelial space. Finally, LDL oxidized by myeloperoxidase (Mox-LDL) activates endothelial cells and induces interleukine-8 (IL-8) secretion by these cells. Mox-LDL effects on monocyte are similar and activate tumor-necrosis factor-α (TNFα) secretion by these cells. In turn, IL-8 and TNFα activate monocytes and endothelial cells, respectively. Mox-LDL also inhibits fibrinolysis process via endothelial cell interaction.