RT Journal Article
T1 Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model
A1 Gómez Hernández, María De La Almudena
A1 Heras Jiménez, Natalia De Las
A1 López-Pastor, Andrea R.
A1 García-Gómez, Gema
A1 Infante-Menéndez, Jorge
A1 González-López, Paula
A1 González-Illanes, Tamara
A1 Lahera Julia, Vicente
A1 Benito De Las Heras, Manuel R.
A1 Escribano Illanes, Óscar
AB 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.
SN 2073-4409
YR 2021
FD 2021
LK https://hdl.handle.net/20.500.14352/93612
UL https://hdl.handle.net/20.500.14352/93612
LA eng
NO Gómez-Hernández A, De Las Heras N, López-Pastor AR, García-Gómez G, Infante-Menéndez J, González-López P, et al. Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model. Cells 2021;10:2035. https://doi.org/10.3390/cells10082035.
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Universidad Complutense de Madrid
NO Instituto de Salud Carlos III
NO Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas
DS Docta Complutense
RD 29 sept 2024