Endothelial ENPP2 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 2) Increases Atherosclerosis in Female and Male Mice
| Autor: | Ela Karshovska, Rokia Mohibullah, Mengyu Zhu, Farima Zahedi, Dominique Thomas, Christiana Magkrioti, Claudia Geissler, Remco T.A. Megens, Mariaelvy Bianchini, Maliheh Nazari-Jahantigh, Nerea Ferreirós, Vassilis Aidinis, Andreas Schober |
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| Přispěvatelé: | Biomedische Technologie, RS: Carim - B01 Blood proteins & engineering, Publica |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Male
PROMOTES ATHEROSCLEROSIS OXIDATIVE MODIFICATION bone marrow Mice Knockout ApoE Phosphoric Diester Hydrolases LOW-DENSITY-LIPOPROTEIN endothelial cells LIPID-PEROXIDATION APOLIPOPROTEIN-E RECEPTORS Mice Tamoxifen INFLAMMATION alleles CELLS Animals AUTOTAXIN EXPRESSION Female Pyrophosphatases atherosclerosis Cardiology and Cardiovascular Medicine LYSOPHOSPHATIDIC ACID lysophospholipids |
| Zdroj: | Arteriosclerosis Thrombosis and Vascular Biology, 42(8), 1023-1036. LIPPINCOTT WILLIAMS & WILKINS |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Background: Maladapted endothelial cells (ECs) secrete ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase 2; autotaxin)—a lysophospholipase D that generates lysophosphatidic acids (LPAs). ENPP2 derived from the arterial wall promotes atherogenic monocyte adhesion induced by generating LPAs, such as arachidonoyl-LPA (LPA20:4), from oxidized lipoproteins. Here, we aimed to determine the role of endothelial ENPP2 in the production of LPAs and atherosclerosis. Methods: We quantified atherosclerosis in mice harboring loxP-flanked Enpp2 alleles crossed with Apoe –/– mice expressing tamoxifen-inducible Cre recombinase under the control of the EC-specific bone marrow X kinase promoter after 12 weeks of high-fat diet feeding. Results: A tamoxifen-induced EC-specific Enpp2 knockout decreased atherosclerosis, accumulation of lesional macrophages, monocyte adhesion, and expression of endothelial CXCL (C-X-C motif chemokine ligand) 1 in male and female Apoe –/– mice. In vitro, ENPP2 mediated the mildly oxidized LDL (low-density lipoprotein)-induced expression of CXCL1 in aortic ECs by generating LPA20:4, palmitoyl-LPA (LPA16:0), and oleoyl-LPA (LPA18:1). ENPP2 and its activity were detected on the endothelial surface by confocal imaging. The expression of endothelial Enpp2 established a strong correlation between the plasma levels of LPA16:0, stearoyl-LPA (LPA18:0), and LPA18:1 and plaque size and a strong negative correlation between the LPA levels and ENPP2 activity in the plasma. Moreover, endothelial Enpp2 knockout increased the weight of high-fat diet–fed male Apoe –/– mice. Conclusions: We demonstrated that the expression of ENPP2 in ECs promotes atherosclerosis and endothelial inflammation in a sex-independent manner. This might be due to the generation of LPA20:4, LPA16:0, and LPA18:1 from mildly oxidized lipoproteins on the endothelial surface. |
| Databáze: | OpenAIRE |
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