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Cardiovascular diseases (CVDs) linked to atherosclerosis remains the leading cause of death worldwide. Atherosclerosis is primarily caused by the accumulation of oxidized forms of low density lipoprotein (LDL) in macrophages (MΦs) in the subendothelial layer of arteries leading to foam cell and fatty streak formation. Many studies suggest that LDL that is modified by myeloperoxidase (MPO) is a key player in the development of atherosclerosis. MΦs can adopt a variety of functional phenotypes that include mainly the proinflammatory M1 and the anti-inflammatory M2 MΦ phenotypes which are both implicated in the process of atherogenesis. In fact, MΦs that reside in atherosclerostic lesions were shown to express a variety of phenotypes ranging between the M1- and M2 MΦ types. Recently, we pointed out the involvement of MPO oxidized-LDL (Mox-LDL) in increasing inflammation in MΦs by reducing their secretion of IL-10. Since little is known about Mox-LDL-mediated pro-atherosclerostic responses in MΦs, our study aimed at analyzing the in vitro effects of Mox-LDL at this level through making use of the well-established model of human THP-1-derived Mφs. Our results demonstrate that Mox-LDL has no effect on apoptosis, reactive oxygen species (ROS) generation and cell death in our cell model; yet, interestingly, our results show that Mox-LDL is significantly engulfed at a higher rate in the different MΦ subtypes supporting its key role in foam cell formation during the progression of the disease as well as previous data that were generated using another primary MΦ cell model of atherosclerosis. [ABSTRACT FROM AUTHOR]

Abstract: Background: Sildenafil, vardenafil, and tadalafil are phosphodiesterase type 5 inhibitors (PDE5-Is) usually used in the treatment of erectile dysfunction (ED). Previously, we have shown the presence of myeloperoxidase-modified low-density lipoprotein (Mox-LDL) in the penises of patients with ED, and we have shown the impact of Mox-LDL on cyclic monophosphate (cGMP) level. In vitro, Mox-LDL triggered the inflammatory response by increasing the release of both interleukin 8 (IL-8) and tumor necrosis factor alpha (TNF-α) by endothelial cells (ECs) and monocytes respectively. Objective: To determine whether or not the three therapeutically PDE5-Is protect against the proinflammatory effects of Mox-LDL or TNF-α on ECs. Design, setting, and participants: ECs (EA.hy926) were incubated in the presence of either TNF-α (100pg/ml) or Mox-LDL (200μg/ml) with each of the three PDE5-Is (1μM, 5μM, and 10μM) respectively. IL-8 production was measured in the supernatant after 48h of incubation. Measurements: All experiments were repeated at least three times. Statistical analysis was performed with an ANOVA. Results and limitations: Two-way ANOVA analysis showed that TNF-α alone (p <0.001) or Mox-LDL alone (p <0.001) increased IL-8 production. Sildenafil, vardenafil, or tadalafil alone did not generate an increase of IL-8 production. Tadalafil in combination with Mox-LDL and TNF-α showed a decrease of IL-8 (p <0.05) compared with sildenafil and vardenafil. Conclusions: Among the three available PDE5-Is, tadalafil showed an additional potentially anti-inflammatory effect on relaxation. Those data could be considered for the chronic use of PDE5-Is, but extrapolations of experimental evidence to the clinical setting should be made cautiously. [Copyright &y& Elsevier]

Abstract: Objective: Erectile dysfunction (ED) is a major vascular disorder. Atherosclerosis is closely related to lipoprotein metabolism and especially, oxidative modifications of low-density lipoproteins (LDLs), which are involved in early development of the atherosclerotic lesions. Current major questions include how LDLs are oxidised (OxLDL) in vivo. Myeloperoxidase (MPO) is an enzyme present in the azurophile granules of neutrophils and monocytes that can contribute to LDL oxidation in the presence of H2O2. We have developed a new monoclonal antibody against LDL modified by MPO (Mox-LDL) and have used it on penile biopsies from patients operated on for penile implant. Methods: Seven patients with vascular ED and one impotent patient after radical prostatectomy (RP) underwent biopsy of the cavernous body during penile implant procedures. An immunohistochemical study with a monoclonal antibody against Mox-LDL and an antibody against apoprotein B (ApoB), the protein moiety of LDL, to confirm the presence of LDL was performed. Results: The staining was positive for Mox-LDL and ApoB and was present between the endothelial cells of the sinusoid spaces and the smooth muscle cells in the seven patients with vascular ED. The patient with RP was negative for Mox-LDL. Discussion: Because it is known that modified LDL could decrease nitric oxide production, Mox-LDL could be one of the agents responsible for ED. Further studies are needed to confirm this hypothesis. [Copyright &y& Elsevier]

The oxidation theory proposes that LDL oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis in triggering inflammation. In contrast to the copper-modified LDL, there are few studies using myeloperoxidase-modified LDL (Mox-LDL) as an inflammation inducer. Our aim is to test whether Mox-LDL could constitute a specific inducer of the inflammatory response. Albumin, which is the most abundant protein in plasma and which is present to an identical concentration of LDL in the intima, was used for comparison. The secretion of IL-8 by endothelial cells (Ea.hy926) and TNF-α by monocytes (THP-1) was measured in the cell medium after exposure of these cells to native LDL, native albumin, Mox-LDL, or Mox-albumin. We observed that Mox-LDL induced a 1.5- and 2-fold increase (ANOVA; P < 0.001) in IL-8 production at 100 µg/mL and 200 µg/mL, respectively. The incubation of THP-1 cells with Mox-LDL (100 µg/mL) increased the production of TNF-α 2-fold over the control. Native LDL, albumin, and Mox-albumin showed no effect in either cellular types. The myeloperoxidase-modified LDL increase in cytokine release by endothelial and monocyte cells and by firing both local and systemic inflammation could induce atherogenesis and its development. [ABSTRACT FROM AUTHOR]

The present paradigm of atherogenesis proposes that low density lipoproteins (LDL) are trapped in subendothelial space of the vascular wall where they are oxidized. Myeloperoxidase (MPO) plays a key role in oxidative damage. We propose that LDL oxidation by myeloperoxidase (Mox-LDL) could occur at the surface of the endothelial cells and not restricted to the subendothelial space. The triad constituted by endothelial cells, circulating LDL and MPO in close interaction, constitutes a synergic mechanism for the genesis of Mox-LDL. [Copyright &y& Elsevier]