TY - JOUR
T1 - Endothelial ENPP2 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 2) Increases Atherosclerosis in Female and Male Mice
AU - Karshovska, E.
AU - Mohibullah, R.
AU - Zhu, M.Y.
AU - Zahedi, F.
AU - Thomas, D.
AU - Magkrioti, C.
AU - Geissler, C.
AU - Megens, R.T.A.
AU - Bianchini, M.
AU - Nazari-Jahantigh, M.
AU - Ferreiros, N.
AU - Aidinis, V.
AU - Schober, A.
N1 - Funding Information:
This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) as part of the Collaborative Research Center 1123 (B08), awarded to (B08) A. Schober and (Z01) to R.T.A. Megens; grant number KA 4209/2-1 awarded to E. Karshovska; and the LOEWE (Landes-Offensive zur Entwicklung wissenschaftlicher-ökonomischer Exzellenz) initiative from the State of Hessen (Germany) “Anwendungsorientierte Arzneimittelforschung,” awarded to D. Thomas and N. Ferreirós.
Publisher Copyright:
© 2022 American Heart Association, Inc.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - 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.
AB - 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.
KW - alleles
KW - atherosclerosis
KW - bone marrow
KW - endothelial cells
KW - lysophospholipids
KW - LOW-DENSITY-LIPOPROTEIN
KW - LYSOPHOSPHATIDIC ACID
KW - PROMOTES ATHEROSCLEROSIS
KW - OXIDATIVE MODIFICATION
KW - AUTOTAXIN EXPRESSION
KW - LIPID-PEROXIDATION
KW - APOLIPOPROTEIN-E
KW - RECEPTORS
KW - CELLS
KW - INFLAMMATION
U2 - 10.1161/ATVBAHA.122.317682
DO - 10.1161/ATVBAHA.122.317682
M3 - Article
C2 - 35708027
SN - 1079-5642
VL - 42
SP - 1023
EP - 1036
JO - Arteriosclerosis Thrombosis and Vascular Biology
JF - Arteriosclerosis Thrombosis and Vascular Biology
IS - 8
ER -