Endothelial lipase (EL) and EL-generated lysophosphatidylcholines promote IL-8 expression in endothelial cells

Riederer, Monika; Lechleitner, Margarete; Hrzenjak, Andelko; Koefeler, Harald; Desoyé, Gernot; Heinemann, Ákos; Frank, Saša

doi:10.1016/j.atherosclerosis.2010.11.007

Cited by 34 publications

(24 citation statements)

References 29 publications

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“…VCAM1 is a cell adhesion molecule that mediates adhesion of leukocytes to vascular endothelium, leading to vascular inflammation, one of the early stages in atherosclerosis development. On the other hand, Riederer et al [61] showed the pro-inflammatory side of EL lipase activity. Interleukin 8 (IL-8) is a pro-inflammatory chemokine and is implicated in the pathogenesis of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Genetic and Structure-Function Studies of Missense Mutations in Human Endothelial Lipase

et al. 2013

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Endothelial lipase (EL) plays a pivotal role in HDL metabolism. We sought to characterize EL and its interaction with HDL as well as its natural variants genetically, functionally and structurally. We screened our biethnic population sample (n = 802) for selected missense mutations (n = 5) and identified T111I as the only common variant. Multiple linear regression analyses in Hispanic subjects revealed an unexpected association between T111I and elevated LDL-C (p-value = 0.012) and total cholesterol (p-value = 0.004). We examined lipase activity of selected missense mutants (n = 10) and found different impacts on EL function, ranging from normal to complete loss of activity. EL-HDL lipidomic analyses indicated that EL has a defined remodeling of HDL without exhaustion of the substrate and a distinct and preference for several fatty acids that are lipid mediators and known for their potent pro- and anti-inflammatory properties. Structural studies using homology modeling revealed a novel α/β motif in the C-domain, unique to EL. The EL dimer was found to have the flexibility to expand and to bind various sizes of HDL particles. The likely impact of the all known missense mutations (n = 18) on the structure of EL was examined using molecular modeling and the impact they may have on EL lipase activity using a novel structure-function slope based on their structural free energy differences. The results of this multidisciplinary approach delineated the impact of EL and its variants on HDL. Moreover, the results suggested EL to have the capacity to modulate vascular health through its role in fatty acid-based signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Genetic and Structure-Function Studies of Missense Mutations in Human Endothelial Lipase

et al. 2013

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“…In this study, we provide evidence that the LXR agonist inhibits LPC‐induced IL‐8 overexpression in HUVECs, which has a biological effect on the firm adhesion of monocytes to the endothelial cells. Lysophosphatidylcholine is a major phospholipid component of ox‐LDL that induces IL‐8 expression and drives monocyte adhesion to endothelial cells via Ca 2+ signaling and NF‐κB pathway, which appear to be responsible for early stage atherogenesis . The LPC model in this study provided an opportunity to examine time‐ and dose‐dependent regulatory mechanisms, such as phosphorylation, ubiquitination and SUMOylation of NF‐κB.…”

Section: Discussionmentioning

confidence: 99%

Activation of liver X receptor attenuates lysophosphatidylcholine‐induced IL‐8 expression in endothelial cells via the NF‐κB pathway and SUMOylation

Song

Gao

et al. 2016

J Cellular Molecular Medi

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The liver X receptor (LXR) is a cholesterol‐sensing nuclear receptor that has an established function in lipid metabolism; however, its role in inflammation is elusive. In this study, we showed that the LXR agonist GW3965 exhibited potent anti‐inflammatory activity by suppressing the firm adhesion of monocytes to endothelial cells. To further address the mechanisms underlying the inhibition of inflammatory cell infiltration, we evaluated the effects of LXR agonist on interleukin‐8 (IL‐8) secretion and nuclear factor‐kappa B (NF‐κB) activation in human umbilical vein endothelial cells (HUVECs). The LXR agonist significantly inhibited lysophosphatidylcholine (LPC)‐induced IL‐8 production in a dose‐dependent manner without appreciable cytotoxicity. Western blotting and the NF‐κB transcription activity assay showed that the LXR agonist inhibited p65 binding to the IL‐8 promoter in LPC‐stimulated HUVECs. Interestingly, knockdown of the indispensable small ubiquitin‐like modifier (SUMO) ligases Ubc9 and Histone deacetylase 4 (HDAC4) reversed the increase in IL‐8 induced by LPC. Furthermore, the LPC‐induced degradation of inhibitory κBα was delayed under the conditions of deficient SUMOylation or the treatment of LXR agonist. After enhancing SUMOylation by knockdown SUMO‐specific protease Sentrin‐specific protease 1 (SENP1), the inhibition of GW3965 was rescued on LPC‐mediated IL‐8 expression. These findings indicate that LXR‐mediated inflammatory gene repression correlates to the suppression of NF‐κB pathway and SUMOylation. Our results suggest that LXR agonist exerts the anti‐atherosclerotic role by attenuation of the NF‐κB pathway in endothelial cells.

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“…Compared with that observed in the LPS-untreated effects of LysoPA and LysoPC on inflammatory cytokines and/or ER stress in other cells involved in atherosclerotic diseases. In particular, LysoPA promotes the release of the chemokine CXCL1 and the accumulation of macrophages in the endothelium of atherosclerotic lesions 3,24) , while LysoPC promotes the expression of IL-8, a proinflammatory and proadhesive chemokine 25) . Regarding ER stress, LysoPA reportedly attenuates ER stress and ER stress-associated apoptosis in murine mesenchymal stem cells 26) .…”

Section: The Lysops Receptor Expression Differed Among the Lps-untreamentioning

confidence: 99%

Lysophosphatidylserine has Bilateral Effects on Macrophages in the Pathogenesis of Atherosclerosis

Nishikawa

Kurano

Ikeda

et al. 2015

J Atheroscler Thromb

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Endothelial lipase (EL) and EL-generated lysophosphatidylcholines promote IL-8 expression in endothelial cells

Cited by 34 publications

References 29 publications

Genetic and Structure-Function Studies of Missense Mutations in Human Endothelial Lipase

Genetic and Structure-Function Studies of Missense Mutations in Human Endothelial Lipase

Activation of liver X receptor attenuates lysophosphatidylcholine‐induced IL‐8 expression in endothelial cells via the NF‐κB pathway and SUMOylation

Lysophosphatidylserine has Bilateral Effects on Macrophages in the Pathogenesis of Atherosclerosis

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