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Effects of BM-573 on Endothelial Dependent Relaxation and Increased Blood Pressure at Early Stages of Atherosclerosis.

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Romero, Miguel Leon-Gomez, Elvira Lobysheva, Irina [UCL] Rath, Géraldine Dogné, Jean-Michel Feron, Olivier [UCL] Dessy, Chantal [UCL]

Endothelial dysfunction is considered to be an early event in atherosclerosis and plays a pivotal role in the development, progression and clinical complications of atherosclerosis. Previous studies have shown the beneficial effects of combined inhibition of thromboxane synthase and antagonism of thromboxane receptors by BM-573 on atherosclerosis; however our knowledge about the beneficial effects of BM-573 on endothelial function and increased blood pressure related to early stage of atherosclerosis is limited. In the present study, we investigated the effects of short-term (3μM, 1 hour) and chronic (10mg/L, 8 weeks) treatments with BM-573 on vasodilatory function, nitric oxide (NO) bioavailability, oxidative stress and systolic blood pressure in 15 weeks old apolipoprotein E-deficient (ApoE-KO) mice. ApoE-KO mice showed a reduced endothelium-derived relaxation. In addition, NO bioavailability was reduced and oxidative stress and blood pressure were increased in ApoE-KO mice versus wild-type mice. BM-573 treatments were able to improve the relaxation profile in ApoE-KO mice. Short-term effects of BM-573 were mainly mediated by an increased phosphorylation of both eNOS and Akt, whereas BM-573 in vivo treatment also reduced oxidative stress and restored NO bioavailability. In addition, chronic administration of BM-573 reduced systolic blood pressure in ApoE-KO mice. In conclusion, pharmacological modulation of TxA2 biosynthesis and biological activities by dual TP antagonism/TxAS inhibition with BM-573, already known to prevent plaque formation, has the potential to correct vasodilatory dysfunction at the early stages of atherosclerosis.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2016
Language Anglais
Journal information "PLoS One" - Vol. 11, no.3, p. e0152579 (2016)
Peer reviewed yes
Publisher Public Library of Science
issn 1932-6203
e-issn 1932-6203
Publication status Accepté/Sous presse
Affiliations UCL - SSS/IREC - Institut de recherche expérimentale et clinique
UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique
Links
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Bibliographic reference Romero, Miguel ; Leon-Gomez, Elvira ; Lobysheva, Irina ; Rath, Géraldine ; Dogné, Jean-Michel ; et. al. Effects of BM-573 on Endothelial Dependent Relaxation and Increased Blood Pressure at Early Stages of Atherosclerosis.. In: PLoS One, Vol. 11, no.3, p. e0152579 (2016)
Permanent URL http://hdl.handle.net/2078.1/173190