Pleiotropism of losartan and its metabolites against cardiopulmonary diseases : small chemical differences, major biological impacts
department or school: Medicine, Faculty of
department or school: Anesthesiology, Pharmacology and Therapeutics, Department of
data provider: DSpace
degree campus: UBCV
creator: Sauge, Elodie
issued: 2024-07-08T18:58:36Z
issued: 2024
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Losartan and telmisartan are blood pressure (BP)-lowering angiotensin II (ANGII) type 1 receptor (AT1) blockers (ARBs) with unexpected therapeutic properties in settings not linked to high BP. ARB pleiotropism is complex, however previous studies have revealed that ARBs can activate endothelial function in vivo by promoting the release of protective vasodilatory nitric oxide (NO) in fashions that may be independent of their ANGII/AT1-blocking effects. As a partial prodrug, losartan is first metabolized into EXP3179, which has traditionally been considered a non-AT1-blocking molecule, followed by conversion into EXP3174, the predominant AT1 blocker. We hypothesized that EXP3179 is the elusive metabolite behind losartan's unexpected NO-activating properties. To test this hypothesis, wild-type and transgenic mice and tissues were treated with losartan, EXP3179 and EXP3174. We showed that contrary to previous beliefs, EXP3179 has similar AT1-blocking and BP-lowering effects as EXP3174, although only the former has the unique ability to enhance endothelial function. We observed that the endothelial function-enhancing effects of EXP3179 were endothelium removal-sensitive, involved the endothelial NO synthase (eNOS) and endothelium-derived hyperpolarizing factor (EDHF) pathways, and are dependent on an intact caveolae/caveolin-1 system, a critical component of the luminal endothelial membrane’s ability to sense flow. As AT1 antagonists did not diminish EXP3179’s effects on vessel reactivity and NO release, ANGII type 2 receptor (AT2) knock-out mice were used to evaluate whether the NO-potentiating effects of losartan and EXP3179 resulted from an ANGII switch towards protective AT2 signalling or direct AT2 activation. We demonstrated that both losartan and EXP3179 act on the endothelium via an AT2-independent mechanism. Finally, we explored the pleiotropic effects of losartan and the most effective ARB at activating the NO pathway, telmisartan, in mouse models of chronic ob…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/88592
note: PLEIOTROPISM OF LOSARTAN AND ITS METABOLITES AGAINST CARDIOPULMONARY DISEASES: SMALL CHEMICAL DIFFERENCES, MAJOR BIOLOGICAL IMPACTS by Elodie Sauge M.Sc., University of Lausanne, 2018 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Pharmacology and Therapeutics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) June 2024 © Elodie Sauge, 2024 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Pleiotropism of losartan and its metabolites against cardiopulmonary diseases: small chemical differences, major biological impacts submitted by Elodie Sauge in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Pharmacology and Therapeutics Examining Committee: Dr. Pascal Bernatchez, Associate Professor, Department of Pharmacology and Therapeutics, UBC Supervisor Dr. Angela Devlin, Professor, Department of Pediatrics, UBC Supervisory Committee Member Dr. Brian Rodrigues, Professor, Faculty of Pharmaceutical Sciences, UBC University Examiner Dr. Kevin Bennewith, Professor, Department of Pathology and Laboratory Medicine, UBC University Examiner Additional Supervisory Committee Members: Dr. Don D. Sin, Professor, Department of Medicine, UBC Supervisory Committee Member Dr. Kelly M. McNagny, Department of Medical Genetics, UBC Supervisory Committee Member iii Abstract Losartan and telmisartan are blood pressure (BP)-lowering angiotensin II (ANGII) type 1 receptor (AT1) blockers (ARBs) with unexpected therapeutic properties in settings not linked to high BP. ARB pleiotropism is complex, however previous studies have revealed that ARBs can activate endothelial function in vivo by promoting the release of protective vasodilatory nitric oxide (NO) in fashions that may be independent of their ANGII/AT1-blocking effects. As a partial prodrug,…
has type: Thesis/Dissertation
date issued: 2024-11
is shown at: 10.14288/1.0444103
language: eng
degree discipline: Pharmacology and Therapeutics
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Bernatchez, Pascal
type: Text
identifier URI: http://hdl.handle.net/2429/88592