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

Abstract

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.

• Authors: 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
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 42 Issue 8 Pg. 1023-1036 (08 2022) ISSN: 1524-4636 [Electronic] United States
• PMID: 35708027 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lysophospholipids
• Tamoxifen
• Phosphoric Diester Hydrolases
• alkylglycerophosphoethanolamine phosphodiesterase
• Pyrophosphatases

Topics

• Animals
• Atherosclerosis (metabolism)
• Endothelial Cells (metabolism)
• Female
• Lysophospholipids
• Male
• Mice
• Mice, Knockout, ApoE
• Phosphoric Diester Hydrolases (genetics, metabolism)
• Pyrophosphatases (metabolism)
• Tamoxifen