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 TNFα 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.
Highlights
Atherosclerosis is an inflammatory process involving vascular cells, monocytes, T lymphocytes, proinflammatory cytokines, chemoattractant cytokines, and growth factors [1,2,3]
This was first highlighted by Steinberg et al who observed that native low-density lipoprotein (LDL) is not extensively taken up by macrophages and does not lead to foam cell formation even though modified lipoproteins accumulate in these cells [9, 16]
Our group has contributed to this, and we observed that Mox-LDL is present in atherosclerotic lesions [109]
Summary
Atherosclerosis is an inflammatory process involving vascular cells, monocytes, T lymphocytes, proinflammatory cytokines, chemoattractant cytokines (chemokines), and growth factors [1,2,3]. Lesions are found in the aorta of healthy 10-year-old children, in coronary arteries of 20year-old adults, and later in cerebral arteries [7] These lesions can naturally disappear without causing any disorder to the patient or progress of advanced lesions with smooth muscle cell migration and proliferation, foam cell accumulation, and can even lead to plaque rupture and thrombus formation. Resistance of ox-LDL to acidic lysosomal proteolysis via cathepsins has been observed [18] The latter phenomenon increases the risk of LDL accumulation in macrophages and foam cell formation. We will show that Mox-LDL has a key role in triggering the inflammatory response during atherogenesis and has effects on monocytes, macrophages, and endothelial cells and that those effects are different than. Clinical aspects of Mox-LDL are illustrated, focusing on several conditions such as atherosclerosis, erectile dysfunction, dialysis, nonalcoholic fatty liver disease, and sleep disorders
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