Cigarette smoke impact on the pulmonary artery: implications on COPD-related pulmonary hypertension

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 31-03-2022

Detalles Bibliográficos
Autor: Sevilla Montero, Javier
Tipo de recurso: tesis doctoral
Fecha de publicación:2022
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/702647
Acceso en línea:http://hdl.handle.net/10486/702647
Access Level:acceso abierto
Palabra clave:Biociencias Moleculares
Biología y Biomedicina / Biología
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spelling Cigarette smoke impact on the pulmonary artery: implications on COPD-related pulmonary hypertensionSevilla Montero, JavierBiociencias MolecularesBiología y Biomedicina / BiologíaTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 31-03-2022Esta Tesis tiene embargado el acceso al texto completo hasta el 01-10-2023Cigarette smoke (CS) stands out as a fundamental environmental risk factor for chronic obstructive pulmonary disease (COPD). Low O2 levels, resulting from COPD pathognomonic airflow obstruction and/or emphysema, have been conceived as a main agent causing pulmonary artery (PA) thickening and sustained vasoconstriction, and therefore triggering pulmonary hypertension (PH). However, direct CS impact on the PA has also been proposed as another key pathogenic mechanism of COPDrelated PH. Although CS effects on lung inflammation and endothelial dysfunction have been more widely described, the damage on resident PA fibroblasts (PAFib) and smooth muscle cells (PASMC) is largely unknown. Thus, we focused on characterizing the consequences of direct CS exposure on these cells, regarding both PA remodeling and vascular tone dysregulation. Our results showed that CS directly made human PAFib and PASMC themselves senescent, but their secretomes were able to stimulate proliferation onto non CS-exposed cells, which could contribute to in vivo PA remodeling. Additionally, we observed that CS diminished human PASMC contractility, and caused murine PA stiffening with decreased vasoconstriction and vasodilation responses. This was accompanied by diminished voltage-gated K+ (Kv) currents, membrane depolarization and Kv7.4 channel downregulation. Importantly, COPD patients and healthy smokers showed diminished Kv7.4 levels compared to non-smokers, so its dysregulation might indeed occur independently of hypoxia. Oxidative stress might behave as a unifying cause for these alterations, since it could induce cell senescence and indicate a mitochondrial dysfunction with to insufficient ATP production. This could indeed explain the reduced contractility even in a contradictory scenario of reduced Kv currents. Oxidative stress might also make guanylyl cyclase insensitive to nitric oxide and reduce the vasodilation capacity of CS-treated PA. After CS exposure, our data proved increased total and mitochondrial superoxide (O2 ·–) levels, which did not parallel a counterbalancing antioxidant enzymes upregulation in human PA cells. Antioxidant N-acetylcysteine prevented CS-driven senescence development, and mitochondrial O2 ·– chelator mitoTEMPO partially reverted mitochondrial fission and membrane potential depolarization caused by CS. MitoTEMPO, however, did not prevent PA vasoconstriction loss, so CS might cause additional dysfunctions in PASMC contractile machinery, besides mitochondrial damage. Finally, we observed a CS-driven downregulation of Cyb5R3, the enzyme which prevents guanylyl cyclase oxidation in PASMC. Together with decreased Kv currents, this might explain the CS-mediated loss in PA vasodilation we observed. Most importantly, PA vasodilation was recovered after mitoTEMPO treatment. Thus, oxidative stress reduction might protect against PA senescence and insensitivity to vasodilators, and be considered as a novel therapeutic approach in the managing of COPD-related PHCalzada García, María JosefaDepartamento de BioquímicaFacultad de MedicinaHospital Universitario de La Princesa20222022-03-31doctoral thesishttp://purl.org/coar/resource_type/c_db06NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/doctoralThesisapplication/pdfhttp://hdl.handle.net/10486/702647reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7026472026-06-23T12:46:27Z
dc.title.none.fl_str_mv Cigarette smoke impact on the pulmonary artery: implications on COPD-related pulmonary hypertension
title Cigarette smoke impact on the pulmonary artery: implications on COPD-related pulmonary hypertension
spellingShingle Cigarette smoke impact on the pulmonary artery: implications on COPD-related pulmonary hypertension
Sevilla Montero, Javier
Biociencias Moleculares
Biología y Biomedicina / Biología
title_short Cigarette smoke impact on the pulmonary artery: implications on COPD-related pulmonary hypertension
title_full Cigarette smoke impact on the pulmonary artery: implications on COPD-related pulmonary hypertension
title_fullStr Cigarette smoke impact on the pulmonary artery: implications on COPD-related pulmonary hypertension
title_full_unstemmed Cigarette smoke impact on the pulmonary artery: implications on COPD-related pulmonary hypertension
title_sort Cigarette smoke impact on the pulmonary artery: implications on COPD-related pulmonary hypertension
dc.creator.none.fl_str_mv Sevilla Montero, Javier
author Sevilla Montero, Javier
author_facet Sevilla Montero, Javier
author_role author
dc.contributor.none.fl_str_mv Calzada García, María Josefa
Departamento de Bioquímica
Facultad de Medicina
Hospital Universitario de La Princesa
dc.subject.none.fl_str_mv Biociencias Moleculares
Biología y Biomedicina / Biología
topic Biociencias Moleculares
Biología y Biomedicina / Biología
description Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 31-03-2022
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-03-31
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/10486/702647
url http://hdl.handle.net/10486/702647
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
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
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score 15,301603

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