Contribution of a phosphatase-independent activity of smooth muscle cell calcineurin to arterial hypertension

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 20-03-2024

Detalles Bibliográficos
Autor: Sun, Yilin
Tipo de recurso: tesis doctoral
Fecha de publicación:2024
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/713888
Acceso en línea:http://hdl.handle.net/10486/713888
Access Level:acceso embargado
Palabra clave:Biología y Biomedicina / Biología
id ES_dd0f64e20cf85d4e6fec79025542d9ea
oai_identifier_str oai:repositorio.uam.es:10486/713888
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Contribution of a phosphatase-independent activity of smooth muscle cell calcineurin to arterial hypertension
Contribución de la actividad independiente de fosfatasa de la calcineurina de las células del músculo liso a la hipertensión arterial
title Contribution of a phosphatase-independent activity of smooth muscle cell calcineurin to arterial hypertension
spellingShingle Contribution of a phosphatase-independent activity of smooth muscle cell calcineurin to arterial hypertension
Sun, Yilin
Biología y Biomedicina / Biología
title_short Contribution of a phosphatase-independent activity of smooth muscle cell calcineurin to arterial hypertension
title_full Contribution of a phosphatase-independent activity of smooth muscle cell calcineurin to arterial hypertension
title_fullStr Contribution of a phosphatase-independent activity of smooth muscle cell calcineurin to arterial hypertension
title_full_unstemmed Contribution of a phosphatase-independent activity of smooth muscle cell calcineurin to arterial hypertension
title_sort Contribution of a phosphatase-independent activity of smooth muscle cell calcineurin to arterial hypertension
dc.creator.none.fl_str_mv Sun, Yilin
author Sun, Yilin
author_facet Sun, Yilin
author_role author
dc.contributor.none.fl_str_mv Campanero García, Miguel
Redondo Moya, Juan Miguel
Departamento de Bioquímica
Facultad de Medicina
Delgado Canencia, Carmen
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
UAM-CSIC. Centro de Biología Molecular Severo Ochoa (CBM)
dc.subject.none.fl_str_mv Biología y Biomedicina / Biología
topic Biología y Biomedicina / Biología
description Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 20-03-2024
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-03-20
dc.type.none.fl_str_mv doctoral thesis
http://purl.org/coar/resource_type/c_db06
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/713888
url http://hdl.handle.net/10486/713888
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv embargoed access
http://purl.org/coar/access_right/c_f1cf
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/embargoedAccess
rights_invalid_str_mv embargoed access
http://purl.org/coar/access_right/c_f1cf
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv embargoedAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869421825224605696
spelling Contribution of a phosphatase-independent activity of smooth muscle cell calcineurin to arterial hypertensionContribución de la actividad independiente de fosfatasa de la calcineurina de las células del músculo liso a la hipertensión arterialSun, YilinBiología y Biomedicina / BiologíaTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 20-03-2024Esta tesis tiene embargado el acceso al texto completo hasta el 20-09-2025A esta tesis se le ha concedido un nuevo período de embargo hasta el 08-01-2029Arterial hypertension (AHT) is one of the most common chronic diseases in the human population, remaining the leading risk factor for cardiovascular disease (CVD) morbidity and mortality. Despite the availability of a plethora of antihypertensive drugs, a substantial proportion of patients with AHT fail to control their blood pressure to the recommended levels. Understanding the molecular mechanisms that lead to AHT is therefore essential to improve the current therapies for AHT. Angiotensin-II (Ang-II), a critical hypertensive effector of the renin-angiotensin system, activates numerous signaling pathways, including that mediated by the serine/threonine phosphatase calcineurin (Cn). Our previous studies revealed that smooth muscle cell (SMC) Cn plays an essential structural role in vascular contractility and AHT independently of its phosphatase activity. Here, we have investigated the mechanism underlying the structural role of SMC Cn in AHT. By using RNAseq analysis, we found that SMC Cn is required for the regulation of nearly 90% of the genes induced or repressed by Ang-II in the aorta independently of Cn enzymatic activity and that SMC Cn orchestrates a transcriptional program closely related to SMC contractility regulation and AHT. SMC Cn not only mediates the induction of AHT by Ang-II but also reverts AHT in hypertensive mice. Among the genes whose induction by Ang-II requires Cn expression in SMC, but not its activity, we identified Serpine1, the gene encoding plasminogen activator inhibitor type-1 (PAI-1), as a potential mediator of Ang-II-induced hypertension. Indeed, high PAI-1 plasma levels have been reported earlier in AHT patients and we show here that PAI-1 induction by the vasopressor stimulus Ang-II requires Cn expression in SMCs and that Cn deletion in hypertensive mice decreases PAI-1 levels. Of note, TM5441, a pharmacological inhibitor of PAI-1, nearly abolished SMC contractility and sharply reverted Ang-II-induced AHT. We hypothesized that the structural role of Cn in AHT could be mediated by its interaction with other proteins. We therefore used high-throughput proteomics to identify the proteins co-immunoprecipitated with Cn in primary aortic smooth muscle cells and discovered that the serine/threonine-protein kinase 3 (SIK3) associates with Cn. Importantly, SIK3 silencing impaired SMC contractility, nearly blocked PAI-1 induction in SMCs and partially inhibited Ang-II-induced AHT. Together, our results suggest that the structural role of SMC Cn in AHT is mediated through the induction of PAI-1 by a Cn-SIK3 complex. These results provide the basis for developing novel pharmacological therapies for AHT, showing great translational potentialThe work in this Thesis has been supported by “La Caixa” Banking Foundation under the project HR18-00068 (to M.R.C. and J.M.R.); Spanish Ministerio de Ciencia e Innovación grant RTI2018-099246-B-I00 (MICIU/ AEI/FEDER, UE) to J.M.R.; grants PID2020-115217RB-100 and PID2021-122388OB-100 to M.R.C and J.M.R, respectively, funded by MCIN/AEI/10.13039/501100011033; Instituto de Salud Carlos III (CIBER-CV CB16/11/00264) to J.M.R.; and Comunidad de Madrid through the European Social Fund (ESF)-financed program AORTASANA-CM (B2017/BMD-3676) to M.R.C and J.M.R. CBMSO and CNIC are Severo Ochoa Centers of Excellence (CEX2021- 001154-S and CEX-2020-001041-S, respectively)Campanero García, MiguelRedondo Moya, Juan MiguelDepartamento de BioquímicaFacultad de MedicinaDelgado Canencia, CarmenCentro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)UAM-CSIC. Centro de Biología Molecular Severo Ochoa (CBM)20242024-03-20doctoral thesishttp://purl.org/coar/resource_type/c_db06NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/doctoralThesisapplication/pdfhttp://hdl.handle.net/10486/713888reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengembargoed accesshttp://purl.org/coar/access_right/c_f1cfAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/embargoedAccessoai:repositorio.uam.es:10486/7138882026-06-23T12:46:27Z
score 15,81155

Similares en LA Referencia