Susceptibility of actin to modification by 4-hydroxy-2-nonenal

Ozeki, Munetaka; Miyagawa‐Hayashino, Aya; Akatsuka, Shinya; Shirase, Tomoyuki; Lee, Wen-Hua; Uchida, Koji; Toyokuni, Shinya

doi:10.1016/j.jchromb.2005.02.025

Cited by 43 publications

(42 citation statements)

References 26 publications

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“…Finally, there is evidence for beneficial effects of thiol protectants in clinical pharmacology of cardiovascular diseases (51). Additionally, cytoskeletal protein modification by 4-HNE, including actin (12,17,30,31,36) and microtubules (17, 58 -59), may play an important role in the regulation of cell-cell contacts and EC barrier function (13,60). Cross-talk between FAK, integrin, and cytoskeleton has been proposed to be responsible for FAK activation and autophosphorylation by integrin in cell adhesion (33).…”

Section: Discussionmentioning

confidence: 99%

“…Actin microfilaments play a critical role in EC barrier regulation (26 -29). It has been shown that actin is the primary target for 4-HNE (30,31), and 4-HNE modulates actin cytoskeleton (12,17,18,30,31). Because intracellular thiols are involved in 4-HNE-induced activation of MAPKs, here we examined the role of thiol protectants, NAC and MPG, on 4-HNE-mediated actin stress fiber formation in ECs.…”

Section: Volume 281 • Number 46 • November 17 2006mentioning

confidence: 97%

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Redox Regulation of 4-Hydroxy-2-nonenal-mediated Endothelial Barrier Dysfunction by Focal Adhesion, Adherens, and Tight Junction Proteins

Usatyuk

Parinandi

Natarajan

2006

Journal of Biological Chemistry

158

142

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4-Hydroxy-2-nonenal (4-HNE), one of the major biologically active aldehydes formed during inflammation and oxidative stress, has been implicated in a number of cardiovascular and pulmonary disorders. 4-HNE has been shown to increase vascular endothelial permeability; however, the underlying mechanisms are unclear. Hence, in the current study, we tested our hypothesis that 4-HNE-induced changes in cellular thiol redox status may contribute to modulation of cell signaling pathways that lead to endothelial barrier dysfunction. Exposure of bovine lung microvascular endothelial cells (BLMVECs) to 4-HNE induced reactive oxygen species generation, depleted intracellular glutathione, and altered cell-cell adhesion as measured by transendothelial electrical resistance. Pretreatment of BLMVECs with thiol protectants, N-acetylcysteine and mercaptopropionyl glycine, attenuated 4-HNE-induced decrease in transendothelial electrical resistance, reactive oxygen species generation, Michael protein adduct formation, protein tyrosine phosphorylation, activation of ERK, JNK, and p38 MAPK, and actin cytoskeletal rearrangement. Treatment of BLMVECs with 4-HNE resulted in the redistribution of FAK, paxillin, VE-cadherin, ␤-catenin, and ZO-1, and intercellular gap formation. Western blot analyses confirmed the formation of 4-HNE-derived Michael adducts with the focal adhesion and adherens junction proteins. Also, 4-HNE decreased tyrosine phosphorylation of FAK without affecting total cellular FAK contents, suggesting the modification of integrins, which are natural FAK receptors. 4-HNE caused a decrease in the surface integrin in a time-dependent manner without altering total ␣5 and ␤3 integrins. These results, for the first time, revealed that 4-HNE in redox-dependent fashion affected endothelial cell permeability by modulating cell-cell adhesion through focal adhesion, adherens, and tight junction proteins as well as integrin signal transduction that may lead dramatic alteration in endothelial cell barrier dysfunction during heart infarction, brain stroke, and lung diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Volume 281 • Number 46 • November 17 2006mentioning

confidence: 97%

Redox Regulation of 4-Hydroxy-2-nonenal-mediated Endothelial Barrier Dysfunction by Focal Adhesion, Adherens, and Tight Junction Proteins

Usatyuk

Parinandi

Natarajan

2006

Journal of Biological Chemistry

158

142

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“…4-HNE is a potent electrophile that will react with nucleophilic functional groups in DNA as well as Cys, Lys, and His residues within proteins. Proteins documented to be targets for modification by 4-HNE include protein disulfide isomerase, actin, and thioredoxin (Carbone et al, 2005;Ozeki et al, 2005;Fang and Holmgren, 2006). Consistent with the potent electrophilic properties of 4-HNE, proteins modified by this biogenic aldehyde displayed compromised function.…”

Section: Introductionmentioning

confidence: 96%

Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) Inhibition by 4-Hydroxynonenal Leads to Increased Akt Activation in Hepatocytes

et al. 2011

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The production of reactive aldehydes such as 4-hydroxynonenal (4-HNE) is proposed to be an important factor in the etiology of alcoholic liver disease. To understand the effects of 4-HNE on homeostatic signaling pathways in hepatocytes, cellular models consisting of the human hepatocellular carcinoma cell line (HepG2) and primary rat hepatocytes were evaluated. Treatment of both HepG2 cells and primary hepatocytes with subcytotoxic concentrations of 4-HNE resulted in the activation of Akt within 30 min as demonstrated by increased phosphorylation of residues Ser473 and Thr308. Quantification and subsequent immunocytochemistry of phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P 3 [rsqb ] resulted in a 6-fold increase in total PtdIns(3,4,5)P 3 and increased immunostaining at the plasma membrane after 4-HNE treatment. Cotreatment of HepG2 cells with 4-HNE and the phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (Ly294002) or the protein phosphatase 2A (PP2A) inhibitor okadaic acid revealed that the mechanism of activation of Akt is PI3K-dependent and PP2A-independent. Using biotin hydrazide detection, it was established that the incubation of HepG2 cells with 4-HNE resulted in increased carbonylation of the lipid phosphatase known as "phosphatase and tensin homolog deleted on chromosome 10" (PTEN), a key regulator of Akt activation. Activity assays both in HepG2 cells and recombinant PTEN revealed a decrease in PTEN lipid phosphatase activity after 4-HNE application. Mass spectral analysis of 4-HNE-treated recombinant PTEN detected a single 4-HNE adduct. Subsequent analysis of Akt dependent physiological consequences of 4-HNE in HepG2 cells revealed significant increases in the accumulation of neutral lipids. These results provide a potential mechanism of Akt activation and cellular consequences of 4-HNE in hepatocytes. IntroductionOxidative modification of proteins by reactive aldehydes has been implicated in an increasing number of hepatic disease states, including hepatitis C, nonalcoholic steatohepatitis, and chronic alcoholic liver disease (Paradis et al., 1997;Seki et al., 2002;Roede et al., 2008). A documented marker for increased oxidative stress in cells is the presence of elevated levels of 4-hydroxynonenal (4-HNE). Reactive aldehydes such as 4-HNE originate from peroxidation of membrane lipids, including linoleic acid (Poli et al., 2008). 4-HNE is a potent electrophile that will react with nucleophilic functional groups in DNA as well as Cys, Lys, and His residues within proteins. Proteins documented to be targets for modification by 4-HNE include protein disulfide isomerase, actin, Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.110.069534.□ S The online version of this article (available at http://molpharm. aspetjournals.org) contains supplemental material.ABBREVIATIONS: 4-HNE, 4-hydroxynonenal; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PH, Pleckstr...

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“…We are recently challenging this hypothesis since ferric nitrilotriacetate (Fe-NTA)-induced renal cancers are rather homogeneous in histology [17,44]. At the early stage of this rat carcinogenesis model, increased amounts of oxidatively modified DNA bases including 8-oxoguanine [45] and a major lipid peroxidation product, 4-hydroxy-2-nonenal, and its proteins modified by this moiety [46][47][48][49] are observed.…”

Section: Oxidative Stress and Genomementioning

confidence: 99%

What has been Learned from the Studies of Oxidative Stress-induced Carcinogenesis: Proposal of the Concept of Oxygenomics

Toyokuni

Akatsuka

2006

J. Clin. Biochem. Nutr.

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Summary Epidemiological studies have demonstrated that oxidative stress associated with a variety of pathological conditions is one of the major causes of carcinogenesis. Reactive oxygen and nitrogen species contribute to genomic alterations, presumably followed by selection of the best-adapted proliferating cells in a given environment. Recent data suggest that there exist common signaling pathways for oxidative stress-associated carcinogenesis. So far, oxidative DNA damage has been assumed to be randomly distributed based on in vitro experiments, and localization of oxidative DNA damage in the genome in vivo has rarely been studied. However, by the use of novel techniques in combination with constructed genome databases, it was found that the localization of oxidative DNA appears to be not random in vivo. We propose to call this rather novel research area "oxygenomics". Not a few signaling pathways start from the recognition of DNA damage. Possible underlying principles should be elucidated in association with cell type, the function of each genomic location, and its transcriptional activity as well as chromatin status determining epigenetic information. Furthermore, this concept may contribute to the development of novel oxidative stress biomarkers. Thus, oxygenomics is a promising research area.

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Susceptibility of actin to modification by 4-hydroxy-2-nonenal

Cited by 43 publications

References 26 publications

Redox Regulation of 4-Hydroxy-2-nonenal-mediated Endothelial Barrier Dysfunction by Focal Adhesion, Adherens, and Tight Junction Proteins

Redox Regulation of 4-Hydroxy-2-nonenal-mediated Endothelial Barrier Dysfunction by Focal Adhesion, Adherens, and Tight Junction Proteins

Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) Inhibition by 4-Hydroxynonenal Leads to Increased Akt Activation in Hepatocytes

What has been Learned from the Studies of Oxidative Stress-induced Carcinogenesis: Proposal of the Concept of Oxygenomics

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