Endothelial ENPP2 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 2) Increases Atherosclerosis in Female and Male Mice

Karshovska, Ela; Mohibullah, Rokia; Zhu, Mengyu; Zahedi, Farima; Thomas, Dominique; Magkrioti, Christiana; Geißler, Claudia; Megens, Remco T. A.; Bianchini, Mariaelvy; Nazari-Jahantigh, Maliheh; Ferreiròs, Nerea; Aidinis, Vassilis; Schober, Andreas

doi:10.1161/atvbaha.122.317682

Cited by 12 publications

(11 citation statements)

References 53 publications

(72 reference statements)

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“…Although ATX and LPA are associated reportedly with inflammatory vascular diseases like atherosclerosis, 20,28 their involvement in the alteration of endothelium-dependent vasorelaxation has not yet been investigated. In contrast, the disruptive effect of LPC on vasorelaxation is well-documented; 8,10,11 however, to the best of our knowledge, the potential involvement of ATX and LPA in this process has not been addressed previously.…”

Section: Discussionmentioning

confidence: 99%

Autotaxin–lysophosphatidic acid receptor 5 axis evokes endothelial dysfunction via reactive oxygen species signaling

Janovicz,

Majer,

Kosztelnik

et al. 2023

Exp Biol Med (Maywood)

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Lysophosphatidylcholine (LPC) is a bioactive lipid that has been shown to attenuate endothelium-dependent vasorelaxation contributing to endothelial dysfunction; however, the underlying mechanisms are not well understood. In this study, we investigated the molecular mechanisms involved in the development of LPC-evoked impairment of endothelium-dependent vasorelaxation. In aortic rings isolated from wild-type (WT) mice, a 20-min exposure to LPC significantly reduced the acetylcholine chloride (ACh)–induced vasorelaxation indicating the impairment of normal endothelial function. Interestingly, pharmacological inhibition of autotaxin (ATX) by GLPG1690 partially reversed the endothelial dysfunction, suggesting that lysophosphatidic acid (LPA) derived from LPC may be involved in the effect. Therefore, the effect of LPC was also tested in aortic rings isolated from different LPA receptor knock-out (KO) mice. LPC evoked a marked reduction in ACh-dependent vasorelaxation in Lpar1, Lpar2, and Lpar4 KO, but its effect was significantly attenuated in Lpar5 KO vessels. Furthermore, addition of superoxide dismutase reduced the LPC-induced endothelial dysfunction in WT but not in the Lpar5 KO mice. In addition, LPC increased H2O2 release from WT vessels, which was significantly reduced in Lpar5 KO vessels. Our findings indicate that the ATX–LPA–LPA5 receptor axis is involved in the development of LPC-induced impairment of endothelium-dependent vasorelaxation via LPA5 receptor–mediated reactive oxygen species production. Taken together, in this study, we identified a new pathway contributing to the development of LPC-induced endothelial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Autotaxin–lysophosphatidic acid receptor 5 axis evokes endothelial dysfunction via reactive oxygen species signaling

Janovicz,

Majer,

Kosztelnik

et al. 2023

Exp Biol Med (Maywood)

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“…In addition to serum ATX, endothelial ATX could play a role in local LPA production and atherosclerotic plaque formation in apoE knockout, hypercholesterolaemic mice [ 118 ]. Inhibition of ATX by pipedimic acid was shown to decrease bovine endothelial monolayer permeability after anoxia-reoxygenation treatment and reduce the permeability of perfused rat mesenteric post-capillary venules after ischemia reperfusion injury [ 119 ] ( Figure 1 and Figure 2 ).…”

Section: Covid-19-associated Changes In Autotaxinmentioning

confidence: 99%

COVID-19, Blood Lipid Changes, and Thrombosis

Farooqui

Sun

et al. 2023

Biomedicines

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Although there is increasing evidence that oxidative stress and inflammation induced by COVID-19 may contribute to increased risk and severity of thromboses, the underlying mechanism(s) remain to be understood. The purpose of this review is to highlight the role of blood lipids in association with thrombosis events observed in COVID-19 patients. Among different types of phospholipases A2 that target cell membrane phospholipids, there is increasing focus on the inflammatory secretory phospholipase A2 IIA (sPLA2-IIA), which is associated with the severity of COVID-19. Analysis indicates increased sPLA2-IIA levels together with eicosanoids in the sera of COVID patients. sPLA2 could metabolise phospholipids in platelets, erythrocytes, and endothelial cells to produce arachidonic acid (ARA) and lysophospholipids. Arachidonic acid in platelets is metabolised to prostaglandin H2 and thromboxane A2, known for their pro-coagulation and vasoconstrictive properties. Lysophospholipids, such as lysophosphatidylcholine, could be metabolised by autotaxin (ATX) and further converted to lysophosphatidic acid (LPA). Increased ATX has been found in the serum of patients with COVID-19, and LPA has recently been found to induce NETosis, a clotting mechanism triggered by the release of extracellular fibres from neutrophils and a key feature of the COVID-19 hypercoagulable state. PLA2 could also catalyse the formation of platelet activating factor (PAF) from membrane ether phospholipids. Many of the above lipid mediators are increased in the blood of patients with COVID-19. Together, findings from analyses of blood lipids in COVID-19 patients suggest an important role for metabolites of sPLA2-IIA in COVID-19-associated coagulopathy (CAC).

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“…Karshovska et al [24 ▪▪ ] reported that a tamoxifen-induced endothelial cell-specific Enpp2 knockout decreased atherosclerosis plaque area, decreased macrophages in lesions, decreased monocyte adhesion, and decreased endothelial expression of C-X-C motif chemokine ligand 1 (CXCL1) in male and female Apoe-/- mice. In vitro , it was shown that Enpp2 mediated mildly oxidized LDL-induced expression of CXCL1 in aortic endothelial cells by generating LPA 20:4, LPA 16:0 and LPA 18:1 [24 ▪▪ ]. Autotaxin was detected on the endothelial surface, and expression of endothelial Enpp2 strongly correlated with plasma levels of LPA16:0, LPA 18:0 and LPA18:1 and aortic plaque size [24 ▪▪ ].…”

Section: Enodthelial Specific Knockout Of Enpp2mentioning

confidence: 99%

“…In vitro , it was shown that Enpp2 mediated mildly oxidized LDL-induced expression of CXCL1 in aortic endothelial cells by generating LPA 20:4, LPA 16:0 and LPA 18:1 [24 ▪▪ ]. Autotaxin was detected on the endothelial surface, and expression of endothelial Enpp2 strongly correlated with plasma levels of LPA16:0, LPA 18:0 and LPA18:1 and aortic plaque size [24 ▪▪ ]. It was concluded that endothelial autotaxin promotes atherosclerosis in both male and female mice due to the generation of LPA20:4, LPA16:0 and LPA18:1 from mildly oxidized lipoproteins located on the endothelial surface [24 ▪▪ ].…”

Section: Enodthelial Specific Knockout Of Enpp2mentioning

confidence: 99%

The multiple roles of lysophosphatidic acid in vascular disease and atherosclerosis

Chattopadhyay

Reddy

Fogelman

2023

Current Opinion in Lipidology

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Purpose of review To explore the multiple roles that lysophosphatidic acid (LPA) plays in vascular disease and atherosclerosis. Recent findings A high-fat high-cholesterol diet decreases antimicrobial activity in the small intestine, which leads to increased levels of bacterial lipopolysaccharide in the mucus of the small intestine and in plasma that increase systemic inflammation, and enhance dyslipidemia and aortic atherosclerosis. Decreasing LPA production in enterocytes reduces the impact of the diet. LPA signaling inhibits glucagon-like peptide 1 secretion, promotes atherosclerosis, increases vessel permeability and infarct volume in stroke, but protects against abdominal aortic aneurysm formation and rupture. Acting through the calpain system in lymphatic endothelial cells, LPA reduces the trafficking of anti-inflammatory Treg lymphocytes, which enhances atherosclerosis. Acting through LPA receptor 1 in cardiac lymphatic endothelial cells and fibroblasts, LPA enhances hypertrophic cardiomyopathy. Summary LPA plays multiple roles in vascular disease and atherosclerosis that is cell and context dependent. In some settings LPA promotes these disease processes and in others it inhibits the disease process. Because LPA is so ubiquitous, therapeutic approaches targeting LPA must be as specific as possible for the cells and the context in which the disease process occurs.

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Endothelial ENPP2 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 2) Increases Atherosclerosis in Female and Male Mice

Cited by 12 publications

References 53 publications

Autotaxin–lysophosphatidic acid receptor 5 axis evokes endothelial dysfunction via reactive oxygen species signaling

Autotaxin–lysophosphatidic acid receptor 5 axis evokes endothelial dysfunction via reactive oxygen species signaling

COVID-19, Blood Lipid Changes, and Thrombosis

The multiple roles of lysophosphatidic acid in vascular disease and atherosclerosis

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