Arachidonate 15-Lipoxygenase Type B Knockdown Leads to Reduced Lipid Accumulation and Inflammation in Atherosclerosis

Magnusson, Lena; Lundqvist, Annika; Karlsson, Merja Nurkkala; Skålén, Kristina; Levin, Max; Wiklund, Olov; Borén, Jan; Hultén, Lillemor Mattsson

doi:10.1371/journal.pone.0043142

Cited by 45 publications

(47 citation statements)

References 28 publications

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“…In addition, 15-LOX-2 is expressed in macrophages (7,34,35), and expression is regulated by hypoxia-inducible factor-1␣ (35). Moreover, knockdown of 15-LOX-2 expression in human primary macrophages and in mice (in this case, the target was 8-LOX, the murine homologue of 15-LOX-2) decreased lipid accumulation and inflammation, hallmarks of atherosclerosis (8).…”

Section: Discussionmentioning

confidence: 99%

“…However, silencing expression of murine ALOX15B (which produces 8-HPETE from AA rather than 15-HPETE) mitigated plaque formation (8). These studies appear to be at odds: the former indicates that it is the product of a 15-LOX that promotes plaque formation, whereas one might infer from the latter studies that 8-HETE should be the proinflammatory lipid mediator in the mouse model.…”

Section: -Lox-2 and 5-lox Differ In The Orientations Of Theirmentioning

confidence: 99%

“…ALOX15A mRNA is not detected above control levels in either case (6). More recently, Magnusson et al (8) demonstrated that silencing production of the ALOX15B protein in human macrophages decreased cellular lipid accumulation, the precipitating factor in foam cell formation. Finally, 15S-hydroxyeicosatetraenoic acid (HETE), derived through non-enzymatic reduction of the product of the 15-LOX reaction, has been shown to promote formation of atherosclerotic lesions in a mouse model system (9).…”

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confidence: 97%

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The Structure of Human 15-Lipoxygenase-2 with a Substrate Mimic

Kobe

Neau

Mitchell

et al. 2014

Journal of Biological Chemistry

119

146

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Background: 15-Lipoxygenase-2 is linked to atherosclerotic plaque formation; the homologous enzyme 5-lipoxygenase initiates the synthesis of proinflammatory leukotrienes. Results: We determined the crystal structure of 15-LOX-2 in the presence of a substrate mimic. Conclusion: 15-Lipoxygenase-2 and 5-lipoxgenase display active site variations that confer distinct product specificities. Significance: These differences can be exploited for the design of isoform-specific anti-inflammatories.

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Section: Discussionmentioning

confidence: 99%

Section: -Lox-2 and 5-lox Differ In The Orientations Of Theirmentioning

confidence: 99%

mentioning

confidence: 97%

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The Structure of Human 15-Lipoxygenase-2 with a Substrate Mimic

Kobe

Neau

Mitchell

et al. 2014

Journal of Biological Chemistry

119

146

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“…These data support our suggestion that m8S-LOX may generate 15-HETE in a cellular context, because these knock-out mice generate 15-HETE in the absence of the 15-LOX-1 counterpart (ϳ40% sequence identity with 15-LOX-2). Moreover, Magnusson et al (6) have demonstrated that ALOX15B gene-silencing experiments in human primary macrophages decrease cellular lipid accumulation and that the equivalent knockdown in a murine model (LDLR Ϫ/Ϫ ) leads to a reduction in markers of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Membrane-dependent Activities of Human 15-LOX-2 and Its Murine Counterpart

Bender

Schexnaydre

Murphy

et al. 2016

Journal of Biological Chemistry

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The enzyme encoded by the ALOX15B gene has been linked to the development of atherosclerotic plaques in humans and in a mouse model of hypercholesterolemia. In vitro, these enzymes, which share 78% sequence identity, generate distinct products from their substrate arachidonic acid: the human enzyme, a 15-S-hydroperoxy product; and the murine enzyme, an 8-S-product. We probed the activities of these enzymes with nanodiscs as membrane mimics to determine whether they can access substrate esterified in a bilayer and characterized their activities at the membrane interface. We observed that both enzymes transform phospholipid-esterified arachidonic acid to a 15-S-product. Moreover, when expressed in transfected HEK cells, both enzymes result in significant increases in the amounts of 15-hydroxyderivatives of eicosanoids detected. In addition, we show that 15-LOX-2 is distributed at the plasma membrane when the HEK293 cells are stimulated by the addition Ca 2؉ ionophore and that cellular localization is dependent upon the presence of a putative membrane insertion loop. We also report that sequence differences between the human and mouse enzymes in this loop appear to confer distinct mechanisms of enzyme-membrane interaction for the homologues.A macrophage 2 activity has been linked to elevated levels of oxidized lipids through several experimental approaches that include the heterologous expression of human 15-LOX in a mouse model of hyperlipidemia (1) and pharmacological inhibition of 15-LOX activity (2, 3). These lipid oxidation products can enter the extracellular pool of cholesterol esters transported by LDL (4) and promote the pathological consequences of elevated LDL cholesterol levels (5). Macrophages that take up LDL laden with oxidized lipids are transformed to foam cells, an event that leads to further inflammation and apoptosis and results in the formation of atherosclerotic plaques. Recently, Magnusson et al. (6) demonstrated that silencing production of 15-LOX-2 (the product of the ALOX15B gene) in human macrophages decreased cellular lipid accumulation, the precipitating factor in foam cell formation. These results suggest that inhibition of 15-LOX-2 is a strategy for mitigating the development of cardiovascular disease.Lipoxygenases oxygenate arachidonic acid (AA) to form a stereo-and regiospecific isomer of hydroperoxyeicosatetraenoic acid (HpETE), and isoforms are named according to which carbon atom is oxygenated (for review see Refs. 7 and 8).In general, within a species, lipoxygenases that differ in regiospecificity share ϳ40% sequence identity. In contrast, betweenspecies LOX homologues are expected to share ϳ75% or better sequence identity and generate the same HpETE isomer. The mouse homologue of human 15-LOX-2, however, is an 8-LOX (m8S-LOX) with free AA as the substrate, and this altered regiospecificity appears to be unique to the mouse enzyme (9). We asked whether at the membrane and in a cellular context the mouse enzyme might also generate a 15-HpETE product. This information might prov...

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“…Besides, 4 overlapped genes (A LOX15B, CCL11, NLRP2 and SERPINA3) were identified in IIA vs. IB and IIA vs. IIB. The knockdown of the human arachidonate 15-lipoxygenase type B (ALOX15B) was reported to reduce the inflammation and lipid accumulation, suggesting its active pro-inflammatory and proatherogenic role (20). Pyrin domain-containing protein 2 (NALP2) was characterized by an N-terminal pyrin domain (PYD).…”

Section: Discussionmentioning

confidence: 99%

Identification of miRNAs and differentially expressed genes in early phase non-small cell lung cancer

Tian

Liu²,

Pei

et al. 2016

Oncology Reports

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Abstract.To explore the potential therapeutic targets of early-stage non-small cell lung cancer (NSCLC), gene microarray analysis was conducted. The microarray data of NSCLC in stage IA, IB, IIA, and IIB (GSE50081), were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) in IB vs. IA, IIA vs. IB, IIB vs. IIA were screened out via R. ToppGene Suite was used to get the enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the DEGs. The GeneCoDis3 database and Cytoscape software were used to construct the transcriptional regulatory network. In total, 25, 17 and 14 DEGs were identified in IB vs. IA, IIA vs. IB, IIB vs. IIA of NSCLC, respectively. Some GO terms and pathways (e.g., extracellular space, alveolar lamellar body, bioactivation via cytochrome P450 pathway) were found significantly enriched in DEGs. Genes S100P, ALOX15B, CCL11, NLRP2, SERPINA3, FoxO4 and hsa-miR-491 may play important roles in the development of early-stage NSCLC. Thus, by bioinformatics analysis the key genes and biological processes involving in the development of early-stage NSCLC could be established, providing more potential references for the therapeutic targets.

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Arachidonate 15-Lipoxygenase Type B Knockdown Leads to Reduced Lipid Accumulation and Inflammation in Atherosclerosis

Cited by 45 publications

References 28 publications

The Structure of Human 15-Lipoxygenase-2 with a Substrate Mimic

The Structure of Human 15-Lipoxygenase-2 with a Substrate Mimic

Membrane-dependent Activities of Human 15-LOX-2 and Its Murine Counterpart

Identification of miRNAs and differentially expressed genes in early phase non-small cell lung cancer

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