Hydroxyalkenals and oxidized phospholipids modulation of endothelial cytoskeleton, focal adhesion and adherens junction proteins in regulating endothelial barrier function

Abstract

Lipid peroxidation of polyunsaturated fatty acids generates bioactive aldehydes, which exhibit pro- and anti-inflammatory effects in cells and tissues. Accumulating evidence indicates that 4-hydroxynonenal (4-HNE), a major aldehyde derived from lipid peroxidation of n-6 polyunsaturated fatty acids trigger signals that modulates focal adhesion and adherens junction proteins thereby inducing endothelial barrier dysfunction. Similarly, oxidized phospholipids (Ox-PLs) generated by lipid peroxidation of phospholipids with polyunsaturated fatty acids have been implicated in atherogenesis, inflammation and gene expression. Interestingly, physiological concentration of Ox-PLs are anti-inflammatory and protect against endotoxin- and ventilator-associated acute lung injury. Thus, excess generation of bioactive hydroxyalkenals and Ox-PLs during oxidative stress contributes to pathophysiology of various diseases by modulating signaling pathways that regulate pro- and anti-inflammatory responses and barrier regulation. This review summarizes the role of 4-HNE and Ox-PLs affecting cell signaling pathways and endothelial barrier dysfunction through modulation of the activities of proteins/enzymes by Michael adducts formation, enhancing the level of protein tyrosine phosphorylation of the target proteins, and by reorganization of cytoskeletal, focal adhesion, and adherens junction proteins. A better understanding of molecular mechanisms of hydroxyalkenals- and Ox-PLs-mediated pro-and anti-inflammatory responses and barrier function may lead to development of novel therapies to ameliorate oxidative stress related cardio-pulmonary disorders.

4-Hydroxynonenal Promotes Growth and Angiogenesis of Breast Cancer Cells through HIF-1α Stabilization

“…4-HNE can bind to thiol (SH) and amino (NH2) groups of cysteine, lysine and histidine residues by Michael addition reaction and form a covalent bond between 4-HNE and the amino acid (Usatyuk and Natarajan, 2012). Thus, 4-HNE can increase the oxidative post translational modification (PTM) and alter the function of protein.…”

Peripheral oxidative stress in relapsing–remitting multiple sclerosis

“…The brain is particularly vulnerable to oxidation damage due to: i) elevated use of oxygen; ii) low antioxidant levels; and iii) high phospholipid levels. Peroxidation of membrane lipids results in the generation of oxidized phospholipids (Ox-PL) and reactive aldehydes which may increase blood-brain barrier permeability [7,8]. Recent studies have also shown that Ox-PLs induce monocyte binding to endothelial cells [8].…”

“…Peroxidation of membrane lipids results in the generation of oxidized phospholipids (Ox-PL) and reactive aldehydes which may increase blood-brain barrier permeability [7,8]. Recent studies have also shown that Ox-PLs induce monocyte binding to endothelial cells [8].A number of mechanisms are thought to be involved in the demyelination and neurodegeneration characteristic of MS. Recently, oxidative damage has been associated with mitochondrial injury and energy failure, which may account for certain pathological features of multiple sclerosis, including demyelination, oligodendrocyte apoptosis and astrocyte dysfunction [9].…”

Inflammation-related gene expression by lipid oxidation-derived products in the progression of atherosclerosis

“…The progressive accumulation of these adducts alters normal cell functions, and may lead to cell death [104,[109][110][111]. Nonetheless, at low and noncytotoxic concentrations, these molecules can act as second messengers in signal transduction in physiological and/or pathophysiological conditions [111][112][113][114][115].…”

“…HNE can directly impair the barrier function of the endothelium by increasing its permeability [115]: it may induce changes in cellular thiol redox status, thus perturbing cell signaling pathways and leading to endothelial barrier dysfunction. Following induction of ROS, HNE may affect EC permeability, modulating cell-cell adhesion by suppressing focal adhesion kinase (FAK) phosphorylation, which in turn affects focal adhesion, adherence, and tight junction proteins, as well as integrins, which are natural FAK receptors [121].…”