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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 principales: Gómez-Hernández, Almudena, de las Heras, Natalia, López-Pastor, Andrea R., García-Gómez, Gema, Infante-Menéndez, Jorge, González-López, Paula, González-Illanes, Tamara, Lahera, Vicente, Benito, Manuel, Escribano, Óscar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392327/
https://www.ncbi.nlm.nih.gov/pubmed/34440804
http://dx.doi.org/10.3390/cells10082035
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author Gómez-Hernández, Almudena
de las Heras, Natalia
López-Pastor, Andrea R.
García-Gómez, Gema
Infante-Menéndez, Jorge
González-López, Paula
González-Illanes, Tamara
Lahera, Vicente
Benito, Manuel
Escribano, Óscar
author_facet Gómez-Hernández, Almudena
de las Heras, Natalia
López-Pastor, Andrea R.
García-Gómez, Gema
Infante-Menéndez, Jorge
González-López, Paula
González-Illanes, Tamara
Lahera, Vicente
Benito, Manuel
Escribano, Óscar
author_sort Gómez-Hernández, Almudena
collection PubMed
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.
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spelling pubmed-83923272021-08-28 Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model Gómez-Hernández, Almudena de las Heras, Natalia López-Pastor, Andrea R. García-Gómez, Gema Infante-Menéndez, Jorge González-López, Paula González-Illanes, Tamara Lahera, Vicente Benito, Manuel Escribano, Óscar Cells Article 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. MDPI 2021-08-09 /pmc/articles/PMC8392327/ /pubmed/34440804 http://dx.doi.org/10.3390/cells10082035 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gómez-Hernández, Almudena
de las Heras, Natalia
López-Pastor, Andrea R.
García-Gómez, Gema
Infante-Menéndez, Jorge
González-López, Paula
González-Illanes, Tamara
Lahera, Vicente
Benito, Manuel
Escribano, Óscar
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
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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392327/
https://www.ncbi.nlm.nih.gov/pubmed/34440804
http://dx.doi.org/10.3390/cells10082035
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