Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones

Cardiovascular disease (CVD) risk shows a clear sexual dimorphism with age, with a lower incidence in young women compared to age-matched men. However, this protection is lost after menopause. We demonstrate that sex-biased sensitivity to the development of CVD with age runs in parallel with changes...

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Autores: Arcones, Alba C., Martínez-Cignoni, Melanie Raquel, Vila-Bedmar, Rocío, Yáñez, Claudia, Lladó, Isabel, Proenza, Ana M., Mayor Jr., Federico, Murga, Cristina
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/263279
Acceso en línea:http://hdl.handle.net/10261/263279
Access Level:acceso abierto
Palabra clave:Sexual dimorphism
Cardiovascular disease
G protein-coupled receptor kinase 2
Estrogens
Mitochondria
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spelling Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian HormonesArcones, Alba C.Martínez-Cignoni, Melanie RaquelVila-Bedmar, RocíoYáñez, ClaudiaLladó, IsabelProenza, Ana M.Mayor Jr., FedericoMurga, CristinaSexual dimorphismCardiovascular diseaseG protein-coupled receptor kinase 2EstrogensMitochondriaCardiovascular disease (CVD) risk shows a clear sexual dimorphism with age, with a lower incidence in young women compared to age-matched men. However, this protection is lost after menopause. We demonstrate that sex-biased sensitivity to the development of CVD with age runs in parallel with changes in G protein-coupled receptor kinase 2 (GRK2) protein levels in the murine heart and that mitochondrial fusion markers, related to mitochondrial functionality and cardiac health, inversely correlate with GRK2. Young female mice display lower amounts of cardiac GRK2 protein compared to age-matched males, whereas GRK2 is upregulated with age specifically in female hearts. Such an increase in GRK2 seems to be specific to the cardiac muscle since a different pattern is found in the skeletal muscles of aging females. Changes in the cardiac GRK2 protein do not seem to rely on transcriptional modulation since adrbk1 mRNA does not change with age and no differences are found between sexes. Global changes in proteasomal or autophagic machinery (known regulators of GRK2 dosage) do not seem to correlate with the observed GRK2 dynamics. Interestingly, cardiac GRK2 upregulation in aging females is recapitulated by ovariectomy and can be partially reversed by estrogen supplementation, while this does not occur in the skeletal muscle. Our data indicate an unforeseen role for ovarian hormones in the regulation of GRK2 protein levels in the cardiac muscle which correlates with the sex-dependent dynamics of CVD risk, and might have interesting therapeutic applications, particularly for post-menopausal women.Agencia Estatal de Investigación (MINECO/FEDER), Spain (grant SAF2017-84125-R to FM and CM and grant SAF2016-80384 R to ILL and AMP); the CIBER de Enfermedades Cardiovasculares (CIBERCV, Instituto de Salud Carlos III) Spain (grant CB16/11/00278 to F.M., co-funded with European FEDER contribution), and the Programa de Actividades en Biomedicina de la Comunidad de Madrid (B2017/BMD-3671-INFLAMUNE to FM) and Fundación Ramón ArecesMultidisciplinary Digital Publishing InstituteMinisterio de Economía y Competitividad (España)Centro de Investigación Biomédica en Red Enfermedades Cardiovaculares (España)Instituto de Salud Carlos IIIComunidad de MadridFundación Ramón ArecesConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220212022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/263279reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.3390/cells10030673Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2632792026-05-22T06:33:51Z
dc.title.none.fl_str_mv Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones
title Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones
spellingShingle Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones
Arcones, Alba C.
Sexual dimorphism
Cardiovascular disease
G protein-coupled receptor kinase 2
Estrogens
Mitochondria
title_short Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones
title_full Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones
title_fullStr Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones
title_full_unstemmed Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones
title_sort Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones
dc.creator.none.fl_str_mv Arcones, Alba C.
Martínez-Cignoni, Melanie Raquel
Vila-Bedmar, Rocío
Yáñez, Claudia
Lladó, Isabel
Proenza, Ana M.
Mayor Jr., Federico
Murga, Cristina
author Arcones, Alba C.
author_facet Arcones, Alba C.
Martínez-Cignoni, Melanie Raquel
Vila-Bedmar, Rocío
Yáñez, Claudia
Lladó, Isabel
Proenza, Ana M.
Mayor Jr., Federico
Murga, Cristina
author_role author
author2 Martínez-Cignoni, Melanie Raquel
Vila-Bedmar, Rocío
Yáñez, Claudia
Lladó, Isabel
Proenza, Ana M.
Mayor Jr., Federico
Murga, Cristina
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Centro de Investigación Biomédica en Red Enfermedades Cardiovaculares (España)
Instituto de Salud Carlos III
Comunidad de Madrid
Fundación Ramón Areces
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Sexual dimorphism
Cardiovascular disease
G protein-coupled receptor kinase 2
Estrogens
Mitochondria
topic Sexual dimorphism
Cardiovascular disease
G protein-coupled receptor kinase 2
Estrogens
Mitochondria
description Cardiovascular disease (CVD) risk shows a clear sexual dimorphism with age, with a lower incidence in young women compared to age-matched men. However, this protection is lost after menopause. We demonstrate that sex-biased sensitivity to the development of CVD with age runs in parallel with changes in G protein-coupled receptor kinase 2 (GRK2) protein levels in the murine heart and that mitochondrial fusion markers, related to mitochondrial functionality and cardiac health, inversely correlate with GRK2. Young female mice display lower amounts of cardiac GRK2 protein compared to age-matched males, whereas GRK2 is upregulated with age specifically in female hearts. Such an increase in GRK2 seems to be specific to the cardiac muscle since a different pattern is found in the skeletal muscles of aging females. Changes in the cardiac GRK2 protein do not seem to rely on transcriptional modulation since adrbk1 mRNA does not change with age and no differences are found between sexes. Global changes in proteasomal or autophagic machinery (known regulators of GRK2 dosage) do not seem to correlate with the observed GRK2 dynamics. Interestingly, cardiac GRK2 upregulation in aging females is recapitulated by ovariectomy and can be partially reversed by estrogen supplementation, while this does not occur in the skeletal muscle. Our data indicate an unforeseen role for ovarian hormones in the regulation of GRK2 protein levels in the cardiac muscle which correlates with the sex-dependent dynamics of CVD risk, and might have interesting therapeutic applications, particularly for post-menopausal women.
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/263279
url http://hdl.handle.net/10261/263279
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.3390/cells10030673
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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