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Updated: Sep 7, 2025
Author Spotlight: Exploring the Relationship Between Lipotoxicity and HFpEF
Published on: March 29, 2024
Endothelial ENPP2 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 2) Increases Atherosclerosis in Female and Male
Ela Karshovska1, Rokia Mohibullah1, Mengyu Zhu1,2
1Institute for Cardiovascular Prevention, University Hospital, Ludwig-Maximilians-University, Munich, Germany (E.K., R.M., M.Z., F.Z., C.G., R.T.A.M., M.B., M.N.-J., A.S.).
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.
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