Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model

Background: Cardiovascular dysfunction is linked to insulin-resistant states. In this paper, we analyzed whether the severe hepatic insulin resistance of an inducible liver-specific insulin receptor knockout (iLIRKO) might generate vascular insulin resistance and dysfunction, and whether insulin rec...

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Autores: Gómez Hernández, María De La Almudena, Heras Jiménez, Natalia De Las, López-Pastor, Andrea R., García-Gómez, Gema, Infante-Menéndez, Jorge, González-López, Paula, González-Illanes, Tamara, Lahera Julia, Vicente, Benito De Las Heras, Manuel R., Escribano Illanes, Óscar
Formato: artículo
Fecha de publicación:2021
País:España
Recursos:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/93612
Acesso em linha:https://hdl.handle.net/20.500.14352/93612
Access Level:acceso abierto
Palavra-chave:577.1
577.2
Insulin resistance
Gene therapy
Atherosclerosis
Endothelial dysfunction
Biología molecular (Farmacia)
Bioquímica (Farmacia)
2415 Biología Molecular
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oai_identifier_str oai:docta.ucm.es:20.500.14352/93612
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spelling Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic ModelGómez Hernández, María De La AlmudenaHeras Jiménez, Natalia De LasLópez-Pastor, Andrea R.García-Gómez, GemaInfante-Menéndez, JorgeGonzález-López, PaulaGonzález-Illanes, TamaraLahera Julia, VicenteBenito De Las Heras, Manuel R.Escribano Illanes, Óscar577.1577.2Insulin resistanceGene therapyAtherosclerosisEndothelial dysfunctionBiología molecular (Farmacia)Bioquímica (Farmacia)2415 Biología MolecularBackground: Cardiovascular dysfunction is linked to insulin-resistant states. In this paper, we analyzed whether the severe hepatic insulin resistance of an inducible liver-specific insulin receptor knockout (iLIRKO) might generate vascular insulin resistance and dysfunction, and whether insulin receptor (IR) isoforms gene therapy might revert it. Methods: We studied in vivo insulin signaling in aorta artery and heart from iLIRKO. Vascular reactivity and the mRNA levels of genes involved in vascular dysfunction were analyzed in thoracic aorta rings by qRT-PCR. Finally, iLIRKO mice were treated with hepatic-specific gene therapy to analyze vascular dysfunction improvement. Results: Our results suggest that severe hepatic insulin resistance was expanded to cardiovascular tissues. This vascular insulin resistance observed in aorta artery from iLIRKO mice correlated with a reduction in both PI3K/AKT/eNOS and p42/44 MAPK pathways, and it might be implicated in their vascular alterations characterized by endothelial dysfunction, hypercontractility and eNOS/iNOS levels’ imbalance. Finally, regarding long-term hepatic expression of IR isoforms, IRA was more efficient than IRB in the improvement of vascular dysfunction observed in iLIRKO mice. Conclusion: Severe hepatic insulin resistance is sufficient to produce cardiovascular insulin resistance and dysfunction. Long-term hepatic expression of IRA restored the vascular damage observed in iLIRKO mice.Universidad Complutense de Madrid20212021-01-0120212021-01-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/93612reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)InglésengB2017 BMD-3684 Not availableRTI-2018-095098-B100 Not available Not availablePR75 18-21572 Not availableSAF2014 51795-R Not availableAgencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 SAF2017-82133-R PAPEL DE LOS MECANISMOS DE DINAMICA Y CONTROL DE CALIDAD MITOCONDRIALES EN LA AMPLIFICACION DE LA TERMOGENESIS FUNCIONAL O DISFUNCIONALMinisterio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available PIE14%2F00061 Molecular links between diabetes and neurodegenerative disordersCIBERDEMPR75 18-21572 Not availableopen 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:20.500.14352/936122026-06-02T12:44:21Z
dc.title.none.fl_str_mv Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model
title Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model
spellingShingle Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model
Gómez Hernández, María De La Almudena
577.1
577.2
Insulin resistance
Gene therapy
Atherosclerosis
Endothelial dysfunction
Biología molecular (Farmacia)
Bioquímica (Farmacia)
2415 Biología Molecular
title_short Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model
title_full Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model
title_fullStr Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model
title_full_unstemmed Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model
title_sort Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model
dc.creator.none.fl_str_mv Gómez Hernández, María De La Almudena
Heras Jiménez, Natalia De Las
López-Pastor, Andrea R.
García-Gómez, Gema
Infante-Menéndez, Jorge
González-López, Paula
González-Illanes, Tamara
Lahera Julia, Vicente
Benito De Las Heras, Manuel R.
Escribano Illanes, Óscar
author Gómez Hernández, María De La Almudena
author_facet Gómez Hernández, María De La Almudena
Heras Jiménez, Natalia De Las
López-Pastor, Andrea R.
García-Gómez, Gema
Infante-Menéndez, Jorge
González-López, Paula
González-Illanes, Tamara
Lahera Julia, Vicente
Benito De Las Heras, Manuel R.
Escribano Illanes, Óscar
author_role author
author2 Heras Jiménez, Natalia De Las
López-Pastor, Andrea R.
García-Gómez, Gema
Infante-Menéndez, Jorge
González-López, Paula
González-Illanes, Tamara
Lahera Julia, Vicente
Benito De Las Heras, Manuel R.
Escribano Illanes, Óscar
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 577.1
577.2
Insulin resistance
Gene therapy
Atherosclerosis
Endothelial dysfunction
Biología molecular (Farmacia)
Bioquímica (Farmacia)
2415 Biología Molecular
topic 577.1
577.2
Insulin resistance
Gene therapy
Atherosclerosis
Endothelial dysfunction
Biología molecular (Farmacia)
Bioquímica (Farmacia)
2415 Biología Molecular
description Background: Cardiovascular dysfunction is linked to insulin-resistant states. In this paper, we analyzed whether the severe hepatic insulin resistance of an inducible liver-specific insulin receptor knockout (iLIRKO) might generate vascular insulin resistance and dysfunction, and whether insulin receptor (IR) isoforms gene therapy might revert it. Methods: We studied in vivo insulin signaling in aorta artery and heart from iLIRKO. Vascular reactivity and the mRNA levels of genes involved in vascular dysfunction were analyzed in thoracic aorta rings by qRT-PCR. Finally, iLIRKO mice were treated with hepatic-specific gene therapy to analyze vascular dysfunction improvement. Results: Our results suggest that severe hepatic insulin resistance was expanded to cardiovascular tissues. This vascular insulin resistance observed in aorta artery from iLIRKO mice correlated with a reduction in both PI3K/AKT/eNOS and p42/44 MAPK pathways, and it might be implicated in their vascular alterations characterized by endothelial dysfunction, hypercontractility and eNOS/iNOS levels’ imbalance. Finally, regarding long-term hepatic expression of IR isoforms, IRA was more efficient than IRB in the improvement of vascular dysfunction observed in iLIRKO mice. Conclusion: Severe hepatic insulin resistance is sufficient to produce cardiovascular insulin resistance and dysfunction. Long-term hepatic expression of IRA restored the vascular damage observed in iLIRKO mice.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-01-01
2021
2021-01-01
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/20.500.14352/93612
url https://hdl.handle.net/20.500.14352/93612
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv B2017 BMD-3684 Not available
RTI-2018-095098-B100 Not available Not available
PR75 18-21572 Not available
SAF2014 51795-R Not available
Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 SAF2017-82133-R PAPEL DE LOS MECANISMOS DE DINAMICA Y CONTROL DE CALIDAD MITOCONDRIALES EN LA AMPLIFICACION DE LA TERMOGENESIS FUNCIONAL O DISFUNCIONAL
Ministerio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available PIE14%2F00061 Molecular links between diabetes and neurodegenerative disorders
CIBERDEMPR75 18-21572 Not available
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.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
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