Cargando…

Impact of sex and sex hormones on pathophysiology and progression of aortic stenosis in a murine model

The lesions observed in AS have been shown to be sex specific, with women presenting extensive fibrotic remodeling while men developing more calcification deposit. We thus aimed to evaluate the influence of sex and sex hormones on the pathophysiology of aortic valve stenosis (AS) in our mouse model...

Descripción completa

Detalles Bibliográficos
Autores principales: Fleury, Marie‐Ange, Annabi, Mohamed‐Salah, Voisine, Martine, Hervault, Maxime, Boilard, Anne‐Julie, Shen, Mylène, Marette, André, Côté, Nancy, Clavel, Marie‐Annick
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9419154/
https://www.ncbi.nlm.nih.gov/pubmed/36029186
http://dx.doi.org/10.14814/phy2.15433
_version_ 1784777114605584384
author Fleury, Marie‐Ange
Annabi, Mohamed‐Salah
Voisine, Martine
Hervault, Maxime
Boilard, Anne‐Julie
Shen, Mylène
Marette, André
Côté, Nancy
Clavel, Marie‐Annick
author_facet Fleury, Marie‐Ange
Annabi, Mohamed‐Salah
Voisine, Martine
Hervault, Maxime
Boilard, Anne‐Julie
Shen, Mylène
Marette, André
Côté, Nancy
Clavel, Marie‐Annick
author_sort Fleury, Marie‐Ange
collection PubMed
description The lesions observed in AS have been shown to be sex specific, with women presenting extensive fibrotic remodeling while men developing more calcification deposit. We thus aimed to evaluate the influence of sex and sex hormones on the pathophysiology of aortic valve stenosis (AS) in our mouse model of AS. LDLr(−/−)ApoB(100/100)IGF‐II(+/−) mice (n = 210) were separated in six different groups: (1) intact male (IM), (2) intact female (IF), (3) castrated male (CM), (4) ovariectomized females (OF), (5) CM with testosterone supplementation (CMT), and (6) OF with 17β‐estradiol supplementation (OFE). Mice were fed a high‐fat/high‐sucrose/high‐cholesterol diet for 6 months. Hemodynamic progression of AS was followed by transthoracic echocardiography (at 12 and 36 weeks) and analyzed in all mice alive at 36 weeks. Aortic valves were collected for histological and digital droplet PCR* analysis. Increases in peak velocity were comparable in IF and IM (24.2 ± 5.7 vs. 25.8 ± 5.3 cm/s; p = 0.68), but IF presented with less severe AS. Between the three groups of male mice, AS progression was more important in IM (increase in peak velocity: 24.2 ± 5.7 cm/s; p < 0.001) compared to CM (6.2 ± 1.4; p = 0.42), and CMT (15.1 ± 3.5; p = 0.002). In the three groups of female mice, there were no statistical differences in AS progression. Digital PCR analysis revealed an important upregulation of the osteogenic gene RunX2 in IM (p < 0.0001) and downregulation of the pro‐calcifying gene ALPL in IF (p < 0.05). Male sex and testosterone play an important role in upregulation of pro‐calcifying genes and hemodynamic progression of AS. However, female mice appeared to be protected against calcification, characterized by downregulation of pro‐osteogenic genes, but presented a similar AS hemodynamic progression.
format Online
Article
Text
id pubmed-9419154
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-94191542022-08-31 Impact of sex and sex hormones on pathophysiology and progression of aortic stenosis in a murine model Fleury, Marie‐Ange Annabi, Mohamed‐Salah Voisine, Martine Hervault, Maxime Boilard, Anne‐Julie Shen, Mylène Marette, André Côté, Nancy Clavel, Marie‐Annick Physiol Rep Original Articles The lesions observed in AS have been shown to be sex specific, with women presenting extensive fibrotic remodeling while men developing more calcification deposit. We thus aimed to evaluate the influence of sex and sex hormones on the pathophysiology of aortic valve stenosis (AS) in our mouse model of AS. LDLr(−/−)ApoB(100/100)IGF‐II(+/−) mice (n = 210) were separated in six different groups: (1) intact male (IM), (2) intact female (IF), (3) castrated male (CM), (4) ovariectomized females (OF), (5) CM with testosterone supplementation (CMT), and (6) OF with 17β‐estradiol supplementation (OFE). Mice were fed a high‐fat/high‐sucrose/high‐cholesterol diet for 6 months. Hemodynamic progression of AS was followed by transthoracic echocardiography (at 12 and 36 weeks) and analyzed in all mice alive at 36 weeks. Aortic valves were collected for histological and digital droplet PCR* analysis. Increases in peak velocity were comparable in IF and IM (24.2 ± 5.7 vs. 25.8 ± 5.3 cm/s; p = 0.68), but IF presented with less severe AS. Between the three groups of male mice, AS progression was more important in IM (increase in peak velocity: 24.2 ± 5.7 cm/s; p < 0.001) compared to CM (6.2 ± 1.4; p = 0.42), and CMT (15.1 ± 3.5; p = 0.002). In the three groups of female mice, there were no statistical differences in AS progression. Digital PCR analysis revealed an important upregulation of the osteogenic gene RunX2 in IM (p < 0.0001) and downregulation of the pro‐calcifying gene ALPL in IF (p < 0.05). Male sex and testosterone play an important role in upregulation of pro‐calcifying genes and hemodynamic progression of AS. However, female mice appeared to be protected against calcification, characterized by downregulation of pro‐osteogenic genes, but presented a similar AS hemodynamic progression. John Wiley and Sons Inc. 2022-08-27 /pmc/articles/PMC9419154/ /pubmed/36029186 http://dx.doi.org/10.14814/phy2.15433 Text en © 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Fleury, Marie‐Ange
Annabi, Mohamed‐Salah
Voisine, Martine
Hervault, Maxime
Boilard, Anne‐Julie
Shen, Mylène
Marette, André
Côté, Nancy
Clavel, Marie‐Annick
Impact of sex and sex hormones on pathophysiology and progression of aortic stenosis in a murine model
title Impact of sex and sex hormones on pathophysiology and progression of aortic stenosis in a murine model
title_full Impact of sex and sex hormones on pathophysiology and progression of aortic stenosis in a murine model
title_fullStr Impact of sex and sex hormones on pathophysiology and progression of aortic stenosis in a murine model
title_full_unstemmed Impact of sex and sex hormones on pathophysiology and progression of aortic stenosis in a murine model
title_short Impact of sex and sex hormones on pathophysiology and progression of aortic stenosis in a murine model
title_sort impact of sex and sex hormones on pathophysiology and progression of aortic stenosis in a murine model
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9419154/
https://www.ncbi.nlm.nih.gov/pubmed/36029186
http://dx.doi.org/10.14814/phy2.15433
work_keys_str_mv AT fleurymarieange impactofsexandsexhormonesonpathophysiologyandprogressionofaorticstenosisinamurinemodel
AT annabimohamedsalah impactofsexandsexhormonesonpathophysiologyandprogressionofaorticstenosisinamurinemodel
AT voisinemartine impactofsexandsexhormonesonpathophysiologyandprogressionofaorticstenosisinamurinemodel
AT hervaultmaxime impactofsexandsexhormonesonpathophysiologyandprogressionofaorticstenosisinamurinemodel
AT boilardannejulie impactofsexandsexhormonesonpathophysiologyandprogressionofaorticstenosisinamurinemodel
AT shenmylene impactofsexandsexhormonesonpathophysiologyandprogressionofaorticstenosisinamurinemodel
AT maretteandre impactofsexandsexhormonesonpathophysiologyandprogressionofaorticstenosisinamurinemodel
AT cotenancy impactofsexandsexhormonesonpathophysiologyandprogressionofaorticstenosisinamurinemodel
AT clavelmarieannick impactofsexandsexhormonesonpathophysiologyandprogressionofaorticstenosisinamurinemodel