Novel Loss-of-Function KCNA5 Variants in Pulmonary Arterial Hypertension

Reduced expression and/or activity of Kv1.5 channels (encoded byKCNA5) is a common hallmark in human or experimentalpulmonary arterial hypertension (PAH). Likewise, genetic variantsinKCNA5have been found in patients with PAH, but theirfunctional consequences and potential impact on the disease arela...

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Autores: Vera Zambrano, Alba, Morales Cano, Daniel, Villegas Esguevillas, Marta, Cruz Utrilla, Alejandro, Fernández Malavé, Edgar Gonzalo, Escribano Subías, María Pilar, Pérez Vizcaíno, Francisco, Cogolludo Torralba, Ángel Luis
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/92546
Acceso en línea:https://hdl.handle.net/20.500.14352/92546
Access Level:acceso abierto
Palabra clave:615.01/.03
KCNA5 variants
Kv1.5
Ion channels
Potassium channels
Pulmonary hypertension
Farmacología (Medicina)
2411.03 Fisiología Cardiovascular
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oai_identifier_str oai:docta.ucm.es:20.500.14352/92546
network_acronym_str ES
network_name_str España
repository_id_str
spelling Novel Loss-of-Function KCNA5 Variants in Pulmonary Arterial HypertensionVera Zambrano, AlbaMorales Cano, DanielVillegas Esguevillas, MartaCruz Utrilla, AlejandroFernández Malavé, Edgar GonzaloEscribano Subías, María PilarPérez Vizcaíno, FranciscoCogolludo Torralba, Ángel Luis615.01/.03KCNA5 variantsKv1.5Ion channelsPotassium channelsPulmonary hypertensionFarmacología (Medicina)2411.03 Fisiología CardiovascularReduced expression and/or activity of Kv1.5 channels (encoded byKCNA5) is a common hallmark in human or experimentalpulmonary arterial hypertension (PAH). Likewise, genetic variantsinKCNA5have been found in patients with PAH, but theirfunctional consequences and potential impact on the disease arelargely unknown. Herein, this study aimed to characterize thefunctional consequences of sevenKCNA5variants found in a cohortof patients with PAH. Potassium currents were recorded by patch-clamp technique in HEK293 cells transfected with wild-type ormutant Kv1.5 cDNA. Flow cytometry, Western blot, and confocalmicroscopy techniques were used for measuring protein expressionand cell apoptosis in HEK293 and human pulmonary artery smoothmuscle cells.KCNA5variants (namely, Arg184Pro and Gly384Arg)found in patients with PAH resulted in a clear loss of potassiumchannel function as assessed by electrophysiological and molecular modeling analyses. The Arg184Pro variant also resulted in apronounced reduction of Kv1.5 expression. Transfection withArg184Pro or Gly384Arg variants decreased apoptosis ofhuman pulmonary artery smooth muscle cells compared withthe wild-type cells, demonstrating thatKCNA5dysfunction inboth variants affects cell viability. Thus, in addition toaffecting channel activity, both variants were associated withimpaired apoptosis, a crucial process linked to the disease. Theestimated prevalence of dysfunctionalKCNA5variants in thePAH population analyzed was around 1%. The data indicatethat someKCNA5variants found in patients with PAH havecritical consequences for channel function, supporting the ideathatKCNA5pathogenic variants may be a causative orcontributing factor for PAH.American Thoracic SocietyUniversidad Complutense de Madrid20232023-03-1420232023-03-14journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/92546reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/925462026-06-02T12:44:21Z
dc.title.none.fl_str_mv Novel Loss-of-Function KCNA5 Variants in Pulmonary Arterial Hypertension
title Novel Loss-of-Function KCNA5 Variants in Pulmonary Arterial Hypertension
spellingShingle Novel Loss-of-Function KCNA5 Variants in Pulmonary Arterial Hypertension
Vera Zambrano, Alba
615.01/.03
KCNA5 variants
Kv1.5
Ion channels
Potassium channels
Pulmonary hypertension
Farmacología (Medicina)
2411.03 Fisiología Cardiovascular
title_short Novel Loss-of-Function KCNA5 Variants in Pulmonary Arterial Hypertension
title_full Novel Loss-of-Function KCNA5 Variants in Pulmonary Arterial Hypertension
title_fullStr Novel Loss-of-Function KCNA5 Variants in Pulmonary Arterial Hypertension
title_full_unstemmed Novel Loss-of-Function KCNA5 Variants in Pulmonary Arterial Hypertension
title_sort Novel Loss-of-Function KCNA5 Variants in Pulmonary Arterial Hypertension
dc.creator.none.fl_str_mv Vera Zambrano, Alba
Morales Cano, Daniel
Villegas Esguevillas, Marta
Cruz Utrilla, Alejandro
Fernández Malavé, Edgar Gonzalo
Escribano Subías, María Pilar
Pérez Vizcaíno, Francisco
Cogolludo Torralba, Ángel Luis
author Vera Zambrano, Alba
author_facet Vera Zambrano, Alba
Morales Cano, Daniel
Villegas Esguevillas, Marta
Cruz Utrilla, Alejandro
Fernández Malavé, Edgar Gonzalo
Escribano Subías, María Pilar
Pérez Vizcaíno, Francisco
Cogolludo Torralba, Ángel Luis
author_role author
author2 Morales Cano, Daniel
Villegas Esguevillas, Marta
Cruz Utrilla, Alejandro
Fernández Malavé, Edgar Gonzalo
Escribano Subías, María Pilar
Pérez Vizcaíno, Francisco
Cogolludo Torralba, Ángel Luis
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 615.01/.03
KCNA5 variants
Kv1.5
Ion channels
Potassium channels
Pulmonary hypertension
Farmacología (Medicina)
2411.03 Fisiología Cardiovascular
topic 615.01/.03
KCNA5 variants
Kv1.5
Ion channels
Potassium channels
Pulmonary hypertension
Farmacología (Medicina)
2411.03 Fisiología Cardiovascular
description Reduced expression and/or activity of Kv1.5 channels (encoded byKCNA5) is a common hallmark in human or experimentalpulmonary arterial hypertension (PAH). Likewise, genetic variantsinKCNA5have been found in patients with PAH, but theirfunctional consequences and potential impact on the disease arelargely unknown. Herein, this study aimed to characterize thefunctional consequences of sevenKCNA5variants found in a cohortof patients with PAH. Potassium currents were recorded by patch-clamp technique in HEK293 cells transfected with wild-type ormutant Kv1.5 cDNA. Flow cytometry, Western blot, and confocalmicroscopy techniques were used for measuring protein expressionand cell apoptosis in HEK293 and human pulmonary artery smoothmuscle cells.KCNA5variants (namely, Arg184Pro and Gly384Arg)found in patients with PAH resulted in a clear loss of potassiumchannel function as assessed by electrophysiological and molecular modeling analyses. The Arg184Pro variant also resulted in apronounced reduction of Kv1.5 expression. Transfection withArg184Pro or Gly384Arg variants decreased apoptosis ofhuman pulmonary artery smooth muscle cells compared withthe wild-type cells, demonstrating thatKCNA5dysfunction inboth variants affects cell viability. Thus, in addition toaffecting channel activity, both variants were associated withimpaired apoptosis, a crucial process linked to the disease. Theestimated prevalence of dysfunctionalKCNA5variants in thePAH population analyzed was around 1%. The data indicatethat someKCNA5variants found in patients with PAH havecritical consequences for channel function, supporting the ideathatKCNA5pathogenic variants may be a causative orcontributing factor for PAH.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-03-14
2023
2023-03-14
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/92546
url https://hdl.handle.net/20.500.14352/92546
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
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
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
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Thoracic Society
publisher.none.fl_str_mv American Thoracic Society
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869406837028159488
score 15.300724

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