Apolipoprotein A-I increases nitric oxide synthesis and vasodilator response in vivo through the activation of Ecto-F1-ATPase / P2Y1 axis

Cabou, C; Honorato, P; Briceño, L; Parada, N; Aguilera, V; Aguayo, C; González, M; Martinez, LO; Radojkovic, C


Aim: The mechanisms by which apoA-I, the major protein of HDL, contributes to endothelium-dependent regulation of the vascular tone is poorly understood. Ecto-F1-ATPase and P2Y ADP-receptors have been described as mediators of protective effects induced by apoA-I on endothelial cells. This study aimed to investigate the effect of apoA-I and the involvement of ecto-F1-ATPase and P2Y ADP-receptors on nitric oxide (NO) production and regulation of vascular tone in vivo. Methods: endothelial nitric oxide synthase (eNOS) activity and NO bioavailability were assessed in vitro using primary human endothelial cells (HUVEC) and ex vivo in NO real-time measurements in aortas isolated from wild-type mice. Changes in the vascular tone were evaluated in vessel reactivity assays, using human umbilical and placenta veins and by assessing femoral blood flow in conscious wild-type mice. Results: ApoA-I increased both eNOS activity and NO production in HUVEC. Aortic NO production was also increased. These effects were blocked by the presence of NOS inhibitors, IF1 (F1-ATPase inhibitor) and MRS2179 (P2Y1 inhibitor). Cangrelor (P2Y12 inhibitor) did not prevent apoA-I induced-NO release. Accordingly, apoA-I produced relaxation in pre-contracted vessels from human origin and increased blood flow of the femoral artery in mice. These effects were blunted with inhibitors of ecto-F1-ATPase / P2Y1 axis. Conclusions: ApoA-I triggers a NO-dependent vasodilator response in a process that depend on ecto-F1-ATPase activity, which generates extracellular ADP and in turn activates P2Y1 ADP-receptor. This work highlight new targets for the development of pharmacological strategies that could reduce the pathogenesis of hypertension and cardiovascular disease.

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Editorial: European Atherosclerosis Society
Fecha de publicación: 2017
Año de Inicio/Término: 23-26 abril
Página final: 1
Financiamiento/Sponsor: European Atherosclerosis Society
URL: https://www.atherosclerosis-journal.com/article/S0021-9150(17)30294-0/fulltext
Notas: 85th Congress of the European Atherosclerosis Society. Trabajo en colaboración con el INSERM U1048, Toulouse, Francia.