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 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.

Peroxidase activation of cytoglobin by anionic phospholipids: Mechanisms and consequences

“…In the absence of artificial exogenous substrates, peroxidases are known to utilize as their substrates either closely associated phospholipids or amino acid residues in the proximity of their catalytic site [27, 28]. Therefore, we further examined the effectiveness of Cygb in peroxidizing three biologically relevant phospholipids, SAPC, SAPA and SAPIP3.…”

“…This pathway includes sequential hydrolysis by one of Ca 2+ -dependent phospholipases A2 followed by the oxygenation of the released arachidonic acid by cyclooxygenases or lipoxygenases. Recently, an alternative Ca 2+ -independent process has been proposed whereby the oxygenation stage occurs within the phospholipid molecule that subsequently undergoes hydrolysis by a Ca 2+ -independent phospholipase A2 to yield eicosanoids [27, 28]. It has been documented that this mechanism can be realized in mitochondria via the oxygenation of polyunsaturated cardiolipins.…”

Increased levels of serum myeloperoxidase in patients with active rheumatoid arthritis

“…For instance, the oxidation of low-density lipoprotein (LDL) by MPO and the subsequent involvement of the oxidized LDL in the formation of atherosclerosis plaques are well described (Malle et al, 2006;Delporte et al, 2013;Shao and Heinecke, 2011). Nonetheless, the overall etiology of MPO-mediated oxidation in cardiovascular diseases remains unclear, since MPO may play a complex role in both anti-inflammation and proinflammation in the pathogenesis of atherosclerosis.…”

Targeting Immunity in End-Stage Renal Disease

“…This leads to enhanced membrane expression of MHC-II, CD80, CD86, and TLR4 [22] and inflammation. Low density lipoproteins (LDLs) are also oxidized to oxLDLs, largely because of lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) [23], which produces highly proinflammatory lysophosphatidylcholine and oxidized free fatty acids [24]. …”