Pharmacological inhibition of the F 1 -ATPase/P2Y 1 pathway suppresses the effect of apolipoprotein A1 on endothelial nitric oxide synthesis and vasorelaxation

Cendrine Cabou 1, 2 Paula Honorato 3 Luis Briceño 3 Lamia Ghezali 1 Thibaut Duparc 1 Marcelo León 3 Guillaume Combes 1 Laure Frayssinhes 1 Audren Fournel 4 Anne Abot 4 Bernard Masri 1 Nicol Parada 3 Valeria Aguilera 3 Claudio Aguayo 3, 5 Claude Knauf 4 Marcelo González 5, 6, 7 Claudia Radojkovic 3, * Laurent Martinez 1, *
* Corresponding author
1 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
2 Faculté de Pharmacie - Département de physiologie humaine [UNIV Paul Sabatier, Toulouse]
3 Faculty of Pharmacy - Department of Clinical Biochemistry and Immunology [Concepción, Chile]
4 IRSD - Institut de Recherche en Santé Digestive
5 GRIVAS Health - Group of Research and Innovation in Vascular Health [Chillan, Chile]
6 Department of Physiology - Vascular Physiology Laboratory [Concepción, Chile]
7 Faculty of Medicine - Department of Obstetrics and Gynecology [Concepción, Chile]
Abstract : AIM: The contribution of apolipoprotein A1 (APOA1), the major apolipoprotein of high-density lipoprotein (HDL), to endothelium-dependent vasodilatation is unclear, and there is little information regarding endothelial receptors involved in this effect. Ecto-F1 -ATPase is a receptor for APOA1, and its activity in endothelial cells is coupled to adenosine diphosphate (ADP)-sensitive P2Y receptors (P2Y ADP receptors). Ecto-F1 -ATPase is involved in APOA1-mediated cell proliferation and HDL transcytosis. Here we investigated the effect of lipid-free APOA1 and the involvement of ecto-F1 -ATPase and P2Y ADP receptors on nitric oxide (NO) synthesis and the regulation of vascular tone. METHOD: NO synthesis was assessed in human endothelial cells from umbilical veins (HUVECs) and isolated mouse aortas. Changes in vascular tone were evaluated by isometric force measurements in isolated human umbilical and placental veins and by assessing femoral artery blood flow in conscious mice. RESULTS: Physiological concentrations of lipid-free APOA1 enhanced endothelial NO synthesis, which was abolished by inhibitors of endothelial nitric oxide synthase (eNOS) and of the ecto-F1 -ATPase/P2Y1 axis. Accordingly, APOA1 inhibited vasoconstriction induced by thromboxane A2 receptor agonist and increased femoral artery blood flow in mice. These effects were blunted by inhibitors of eNOS, ecto-F1 -ATPase and P2Y1 receptor. CONCLUSIONS: Using a pharmacological approach, we thus found that APOA1 promotes endothelial NO production and thereby controls vascular tone in a process that requires activation of the ecto-F1 -ATPase/P2Y1 pathway by APOA1. Pharmacological targeting of this pathway with respect to vascular diseases should be explored. This article is protected by copyright. All rights reserved.
Keywords : purinergic receptors endothelial cells Apolipoprotein A1 nitric oxide F1-ATPase
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Cendrine Cabou, Paula Honorato, Luis Briceño, Lamia Ghezali, Thibaut Duparc, et al.. Pharmacological inhibition of the F 1 -ATPase/P2Y 1 pathway suppresses the effect of apolipoprotein A1 on endothelial nitric oxide synthesis and vasorelaxation. Acta Physiologica, Wiley, 2019, 1, pp.e13268. ⟨10.1111/apha.13268⟩. ⟨inserm-02074732⟩

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