4-hydroxy-2-nonenal upregulates and phosphorylates cytosolic phospholipase A2 in cultured Ra2 microglial cells via MAPK pathways

Shibata, Noriyuki; Kato, Yoichiro; Inose, Yuri; Hiroi, Atsuko; Yamamoto, Tomoko; Morikawa, Shunichi; Sawada, Makoto; Kobayashi, Makio

doi:10.1111/j.1440-1789.2010.01139.x

Cited by 20 publications

(13 citation statements)

References 36 publications

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“…The increase of apoptosis in Gsta 4 null MEF by 4-HNE was associated with the enhanced accumulation of 4-HNE-protein adducts, DNA damage, and the activation of caspases-3, -8, and -9 [214]. 4-HNE upregulates and phosphorylates cytosolic phospholipase A-2 (cPLA-2) in cultured microglial cell line (Ra2) via the ERK and p38 MAPK pathways [278]. cPLA is a proinflammatory enzyme that stimulate AA- release by hydrolyzes glycerophospholipids with AA in the sn -2 position.…”

Section: Lipids Damage By Reactive Oxygen Speciesmentioning

confidence: 99%

Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal

Ayala

Muñoz

Argüelles

2014

Oxidative Medicine and Cellular Longevity

4,498

3,003

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Lipid peroxidation can be described generally as a process under which oxidants such as free radicals attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs). Over the last four decades, an extensive body of literature regarding lipid peroxidation has shown its important role in cell biology and human health. Since the early 1970s, the total published research articles on the topic of lipid peroxidation was 98 (1970–1974) and has been increasing at almost 135-fold, by up to 13165 in last 4 years (2010–2013). New discoveries about the involvement in cellular physiology and pathology, as well as the control of lipid peroxidation, continue to emerge every day. Given the enormity of this field, this review focuses on biochemical concepts of lipid peroxidation, production, metabolism, and signaling mechanisms of two main omega-6 fatty acids lipid peroxidation products: malondialdehyde (MDA) and, in particular, 4-hydroxy-2-nonenal (4-HNE), summarizing not only its physiological and protective function as signaling molecule stimulating gene expression and cell survival, but also its cytotoxic role inhibiting gene expression and promoting cell death. Finally, overviews of in vivo mammalian model systems used to study the lipid peroxidation process, and common pathological processes linked to MDA and 4-HNE are shown.

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Section: Lipids Damage By Reactive Oxygen Speciesmentioning

confidence: 99%

Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal

Ayala

Muñoz

Argüelles

2014

Oxidative Medicine and Cellular Longevity

4,498

3,003

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“…On the other hand, Song et al [65] reported that HNE could activate JNK via activating an upstream kinase called stress-activated protein kinase kinase-1 (SPKK1). Similarly, HNE activates ERK via activating MEK1/2 and P38MAPK via activating MKK3/6 [66, 67]. However, it is not clear how HNE activates upstream kinases of ERK and MAPK.…”

Section: Lipid Aldehydes In Nf-κb Mediated Cell Signalingmentioning

confidence: 99%

Regulation of NF-B-Induced Inflammatory Signaling by Lipid Peroxidation-Derived Aldehydes

Yadav

Ramana

2013

Oxidative Medicine and Cellular Longevity

162

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Oxidative stress plays a critical role in the pathophysiology of a wide range of diseases including cancer. This view has broadened significantly with the recent discoveries that reactive oxygen species initiated lipid peroxidation leads to the formation of potentially toxic lipid aldehyde species such as 4-hydroxy-trans-2-nonenal (HNE), acrolein, and malondialdehyde which activate various signaling intermediates that regulate cellular activity and dysfunction via a process called redox signaling. The lipid aldehyde species formed during synchronized enzymatic pathways result in the posttranslational modification of proteins and DNA leading to cytotoxicity and genotoxicty. Among the lipid aldehyde species, HNE has been widely accepted as a most toxic and abundant lipid aldehyde generated during lipid peroxidation. HNE and its glutathione conjugates have been shown to regulate redox-sensitive transcription factors such as NF-κB and AP-1 via signaling through various protein kinase cascades. Activation of redox-sensitive transcription factors and their nuclear localization leads to transcriptional induction of several genes responsible for cell survival, differentiation, and death. In this review, we describe the mechanisms by which the lipid aldehydes transduce activation of NF-κB signaling pathways that may help to develop therapeutic strategies for the prevention of a number of inflammatory diseases.

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“…Oxidation to PUFAs in membrane phospholipids can produce 4-hydroxy-2-nonenal (4-HNE), another reactive lipid peroxidation product which can form protein adducts [75] and thus is used as a good marker for assessing oxidative stress in brain tissue and brain injury [36]. In a study with the Ra2 murine microglial cells, 4-HNE was shown to upregulate cPLA 2 expression as well as increased phosphorylation through a pathway involving ERK1/2 and p38 MAPK [75]. …”

Section: Cpla2 In Oxidative and Inflammatory Signaling Pathways In MImentioning

confidence: 99%

Role of Cytosolic Phospholipase A2 in Oxidative and Inflammatory Signaling Pathways in Different Cell Types in the Central Nervous System

et al. 2014

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Phospholipases A2 (PLA2s) are important enzymes for metabolism of fatty acids in membrane phospholipids. Among the three major classes of PLA2s in the mammalian system, the group IV calcium-dependent cytosolic PLA2 alpha (cPLA2α) has received the most attention because it is widely expressed in nearly all mammalian cells and its active participation in cell metabolism. Besides Ca2+ binding to its C-2 domain, this enzyme can undergo a number of cell-specific post-translational modifications, including phosphorylation by protein kinases, S-nitrosylation through interaction with nitric oxide (NO), as well as interaction with other proteins and lipid molecules. Hydrolysis of phospholipids by cPLA2 yields two important lipid mediators, arachidonic acid (AA) and lysophospholipids. While AA is known to serve as a substrate for cyclooxygenases and lipoxygenases, which are enzymes for synthesis of eicosanoids and leukotrienes, lysophospholipids are known to possess detergent-like properties capable of altering micro-domains of cell membranes. An important feature of cPLA2 is its link to cell surface receptors that stimulate signaling pathways associated with activation of protein kinases and production of reactive oxygen species (ROS). In the central nervous system (CNS), cPLA2 activation has been implicated in neuronal excitation, synaptic secretion, apoptosis, cell-cell interaction, cognitive and behavioral function, oxidative-nitrosative stress and inflammatory responses that underline the pathogenesis of a number of neurodegenerative diseases. However, the types of extracellular agonists that target intracellular signaling pathways leading to cPLA2 activation among different cell types and under different physiological and pathological conditions have not been investigated in detail. In this review, special emphasis is given to metabolic events linking cPLA2 to activation in neurons, astrocytes, microglial cells, and cerebrovascular cells. Understanding the molecular mechanism(s) for regulation of this enzyme is deemed important in the development of new therapeutic targets for treatment and prevention of neurodegenerative diseases.

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4-hydroxy-2-nonenal upregulates and phosphorylates cytosolic phospholipase A2 in cultured Ra2 microglial cells via MAPK pathways

Cited by 20 publications

References 36 publications

Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal

Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal

Regulation of NF-B-Induced Inflammatory Signaling by Lipid Peroxidation-Derived Aldehydes

Role of Cytosolic Phospholipase A2 in Oxidative and Inflammatory Signaling Pathways in Different Cell Types in the Central Nervous System

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