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Apold1 deficiency associates with increased arterial thrombosis in vivo


Diaz-Cañestro, Candela; Bonetti, Nicole R; Wüst, Patricia; Nageswaran, Vanasa; Liberale, Luca; Beer, Jürg H; Montecucco, Fabrizio; Lüscher, Thomas F; Bohacek, Johannes; Camici, Giovanni G (2020). Apold1 deficiency associates with increased arterial thrombosis in vivo. European Journal of Clinical Investigation, 50(2):e13191.

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 as well as activation of mitogen-activated protein kinases (MAPKs) and phosphatidyl-inositol-3 kinase (PI3K)/Akt pathways were analyzed 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 to 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.

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 as well as activation of mitogen-activated protein kinases (MAPKs) and phosphatidyl-inositol-3 kinase (PI3K)/Akt pathways were analyzed 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 to 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Molecular Cardiology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Biochemistry
Life Sciences > Clinical Biochemistry
Language:English
Date:1 February 2020
Deposited On:21 Jan 2020 13:32
Last Modified:29 Jul 2020 12:53
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0014-2972
OA Status:Closed
Publisher DOI:https://doi.org/10.1111/eci.13191
PubMed ID:31797367

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Embargo till: 2020-12-03