Apold1 deficiency associates with increased arterial thrombosis in vivo

Candela Diaz-Cañestro, Nicole R. Bonetti, Patricia Wüst, Vanasa Nageswaran, Luca Liberale, Jürg H. Beer, Fabrizio Montecucco, Thomas F. Lüscher, Johannes Bohacek, Giovanni G. Camici

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Abstract

Background: Endothelial cells regulate the formation of blood clots; thus, genes selectively expressed in these cells could primarily determine thrombus formation. Apold1 (apolipoprotein L domain containing 1) is a gene expressed by endothelial cells; whether Apold1 directly contributes to arterial thrombosis has not yet been investigated. Here, we assessed the effect of Apold1 deletion on arterial thrombus formation using an in vivo model of carotid thrombosis induced by photochemical injury. Material and methods: Apold1 knockout (Apold1−/−) mice and wild-type (WT) littermates underwent carotid thrombosis induced by photochemical injury, and time to occlusion was recorded. Tissue factor (TF) activity and activation of mitogen-activated protein kinases (MAPKs) and phosphatidyl-inositol-3 kinase (PI3K)/Akt pathways were analysed by colorimetric assay and Western blotting in both Apold1−/− and WT mice. Finally, platelet reactivity was assessed using light transmission aggregometry. Results: After photochemical injury, Apold1−/− mice exhibited shorter time to occlusion as compared to WT mice. Moreover, TF activity was increased in carotid arteries of Apold1−/− when compared to WT mice. Underlying mechanistic markers such as TF mRNA and MAPKs activation were unaffected in Apold1−/− mice. In contrast, phosphorylation of Akt was reduced in Apold1−/− as compared to WT mice. Additionally, Apold1−/− mice displayed increased platelet reactivity to stimulation with collagen compared with WT animals. Conclusions: Deficiency of Apold1 results in a prothrombotic phenotype, accompanied by increased vascular TF activity, decreased PI3K/Akt activation and increased platelet reactivity. These findings suggest Apold1 as an interesting new therapeutic target in the context of arterial thrombosis.

Original languageEnglish
Article numbere13191
JournalEuropean Journal of Clinical Investigation
Volume50
Issue number2
DOIs
Publication statusPublished - Feb 1 2020

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Keywords

  • Apold1
  • arterial thrombosis
  • platelets
  • tissue factor

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry

Cite this

Diaz-Cañestro, C., Bonetti, N. R., Wüst, P., Nageswaran, V., Liberale, L., Beer, J. H., Montecucco, F., Lüscher, T. F., Bohacek, J., & Camici, G. G. (2020). Apold1 deficiency associates with increased arterial thrombosis in vivo. European Journal of Clinical Investigation, 50(2), [e13191]. https://doi.org/10.1111/eci.13191