Proinflammatory Effects of Advanced Lipoxidation End Products in Monocytes

Background: Malondialdehyde (MDA) released during oxidative stress modifies proteins covalently. Results: The C terminus of complement regulator factor H binds negative patches on MDA-modified proteins, and aHUSrelated mutations affect the interaction. Conclusion: Defects in factor H binding to MDA-modified surfaces might allow deleterious complement activation on them. Significance: MDA-modifications are potentially a new factor in aHUS pathogenesis.

Section: Atypical Hemolytic Uremic Syndrome (Ahus) Is a Severe Thrombmentioning

confidence: 99%

Recognition of Malondialdehyde-modified Proteins by the C Terminus of Complement Factor H Is Mediated via the Polyanion Binding Site and Impaired by Mutations Found in Atypical Hemolytic Uremic Syndrome

Hyvärinen

Uchida

Varjosalo

et al. 2014

“…Various markers of oxidative damage have been identified. Malondialdehyde (MDA), which is one of the most popular markers, was designed to indicate lipid peroxidation (3). Oxidation of amino acid residues such as tyrosine, leading to the formation of dityrosine, protein aggregation, cross-linking, and fragmentation is one type of ROS-mediated protein damage.…”

mentioning

confidence: 99%

Involvement of Oxidative Stress in the Relapse of Acute Myeloid Leukemia

Zhou

Zhang

Wei

et al. 2010

102

The aims of the present study were to determine the level of oxidative stress and the salient factors leading to the relapse of acute myeloid leukemia (AML). Oxidative stress-related parameters and the expressions of specific genes were monitored in 102 cases of AML during a pretreatment period from a primary status to a relapse status. In addition, age-matched healthy subjects were classified as controls. The activities of adenosine deaminase and xanthine oxidase were higher in the relapse condition, whereas those of glutathione peroxidase, monoamine oxidase, and superoxide dismutase, and the total antioxidant capacity (T-AOC) were lower in the primary condition and in controls. Of particular note, levels of advanced oxidation protein products, malondialdehyde, and 8-hydroxydeoxyguanosine were also significantly higher in relapse patients. Furthermore, real-time PCR with SYBR Green revealed that the expression levels of human thioredoxin (TRX) and indoleamine 2,3-dioxygenase were increased in relapse patients. Pearson correlation analysis revealed that the T-AOC was positively correlated with GSH but negatively correlated with 8-OHdG, TRX, and indoleamine 2,3-dioxygenase. Linear regression showed that a low T-AOC and up-regulated TRX expression were the independent factors correlated with relapse. A strong association between oxidative stress and the incidence of disease relapse was observed, which has potential prognosis implications. These results indicate that oxidative stress is a crucial feature of AML and probably affects the development and relapse of AML.

“…3 It also produces a large family of ␥-ketoaldehydes (␥KA), regioisomers that have been given the trivial name of isoketals or isolevuglandins. Exposure of vascular cells to various aldehydes results in endothelial dysfunction, secretion of cytokines, and recruitment of monocytes (1)(2)(3)(4)(5)(6)(7), all of which are key steps in the initiation of the chronic inflammatory conditions leading to atherosclerosis.…”

mentioning

confidence: 99%

Phosphatidylethanolamines Modified by γ-Ketoaldehyde (γKA) Induce Endoplasmic Reticulum Stress and Endothelial Activation

Guo

Chen²,

Cox³

et al. 2011

Peroxidation of plasma lipoproteins has been implicated in the endothelial cell activation and monocyte adhesion that initiate atherosclerosis, but the exact mechanisms underlying this activation remain unclear. Lipid peroxidation generates lipid aldehydes, including the ␥-ketoaldehydes (␥KA), also termed isoketals or isolevuglandins, that readily modify the amine headgroup of phosphatidylethanolamine (PE). We hypothesized that aldehyde modification of PE could mediate some of the proinflammatory effects of lipid peroxidation. We found that PE modified by ␥KA (␥KA-PE) induced THP-1 monocyte adhesion to human umbilical cord endothelial cells. ␥KA-PE also induced expression of adhesion molecules and increased MCP-1 and IL-8 mRNA in human umbilical cord endothelial cells. To determine the structural requirements for ␥KA-PE activity, we tested several related compounds. PE modified by 4-oxo-pentanal induced THP-1 adhesion, but N-glutaroyl-PE and C 18:0 N-acyl-PE did not, suggesting that an N-pyrrole moiety was essential for cellular activity. As the N-pyrrole headgroup might distort the membrane, we tested the effect of the pyrrolePEs on membrane parameters. ␥KA-PE and 4-oxo-pentanal significantly reduced the temperature for the liquid crystalline to hexagonal phase transition in artificial bilayers, suggesting that these pyrrole-PE markedly altered membrane curvature. Additionally, fluorescently labeled ␥KA-PE rapidly internalized to the endoplasmic reticulum (ER); ␥KA-PE induced C/EBP homologous protein CHOP and BiP expression and p38 MAPK activity, and inhibitors of ER stress reduced ␥KA-PE-induced C/EBP homologous protein CHOP and BiP expression as well as EC activation, consistent with ␥KA-PE inducing ER stress responses that have been previously linked to inflammatory chemokine expression. Thus, ␥KA-PE is a potential mediator of the inflammation induced by lipid peroxidation.Lipid peroxidation has been implicated in a host of pathological processes, including inflammation and atherosclerosis, but there is still much that is unknown about the mechanisms linking lipid peroxidation to the activation of inflammatory responses. Lipid peroxidation produces a plethora of lipid aldehydes ( Fig. 1), including malondialdehyde, acrolein, and 4-hydroxynonenal (HNE).3 It also produces a large family of ␥-ketoaldehydes (␥KA), regioisomers that have been given the trivial name of isoketals or isolevuglandins. Exposure of vascular cells to various aldehydes results in endothelial dysfunction, secretion of cytokines, and recruitment of monocytes (1-7), all of which are key steps in the initiation of the chronic inflammatory conditions leading to atherosclerosis.Despite these potentially important inflammatory effects, the mechanisms whereby lipid aldehydes induce their effects on vascular cells are still poorly understood. Significant effort has focused on the effects of protein and DNA modification by lipid aldehydes. However, recent studies have shown that lipid aldehydes, including malondialdehyde, acrolein, HNE, and ␥KA, a...