Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model.
atherosclerosis
endothelial dysfunction
gene therapy
insulin resistance
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
09 08 2021
09 08 2021
Historique:
received:
18
07
2021
revised:
31
07
2021
accepted:
06
08
2021
entrez:
27
8
2021
pubmed:
28
8
2021
medline:
16
11
2021
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 34440804
pii: cells10082035
doi: 10.3390/cells10082035
pmc: PMC8392327
pii:
doi:
Substances chimiques
Insulin
0
Protein Isoforms
0
Receptor, Insulin
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ministerio de Ciencia, Innovación y Universidades
ID : RTI-2018-095098-B100
Organisme : Ministerio de Ciencia e Innovación
ID : SAF2014/51795-R and SAF2017-82133-R
Organisme : Banco Santander
ID : Santander-UCM PR75/18-21572
Organisme : Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas
ID : CIBERDEMPR75/18-21572
Références
Annu Rev Physiol. 2003;65:313-32
pubmed: 12471165
Int J Mol Sci. 2014 Dec 26;16(1):378-400
pubmed: 25548896
Nat Rev Dis Primers. 2017 Jun 15;3:17034
pubmed: 28617414
Cell Metab. 2007 Dec;6(6):446-57
pubmed: 18054314
Circulation. 1990 Aug;82(2):495-506
pubmed: 2372896
J Biol Chem. 2009 Nov 13;284(46):32178-87
pubmed: 19773552
J Clin Endocrinol Metab. 2004 Jul;89(7):3606-9
pubmed: 15240653
Mol Cell. 1998 Nov;2(5):559-69
pubmed: 9844629
Front Med (Lausanne). 2020 Sep 22;7:527059
pubmed: 33102495
Ann Intern Med. 1982 Dec;97(6):833-9
pubmed: 7149491
Am J Physiol. 1989 Nov;257(5 Pt 2):H1327-33
pubmed: 2511765
Gene Ther. 2008 Jun;15(11):831-9
pubmed: 18401432
Cell Metab. 2008 Feb;7(2):125-34
pubmed: 18249172
Eur J Endocrinol. 2005 May;152(5):749-56
pubmed: 15879361
Circulation. 2004 Jan 27;109(3):399-405
pubmed: 14707024
Hypertension. 2007 Apr;49(4):748-60
pubmed: 17309954
Diabetes. 2005 Aug;54(8):2415-23
pubmed: 16046309
Arterioscler Thromb Vasc Biol. 1998 Jan;18(1):20-6
pubmed: 9445251
Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):1340-5
pubmed: 8577766
Dis Model Mech. 2019 Feb 7;12(2):
pubmed: 30642871
Endocrinology. 2006 Aug;147(8):3709-18
pubmed: 16644916
Circulation. 2003 Jun 24;107(24):3073-80
pubmed: 12810606
Diabetes Care. 2001 Apr;24(4):683-9
pubmed: 11315831
Diabetes. 2009 Apr;58(4):820-8
pubmed: 19136656
Cell. 1999 Feb 5;96(3):329-39
pubmed: 10025399
Annu Rev Physiol. 2006;68:123-58
pubmed: 16460269
Circ Res. 2001 Sep 14;89(6):488-95
pubmed: 11557735
Nature. 2013 Jan 10;493(7431):241-5
pubmed: 23302862
Acta Pharmacol Sin. 2010 Sep;31(9):1095-102
pubmed: 20711228
BMJ Open Gastroenterol. 2016 Jul 26;3(1):e000096
pubmed: 27493762
Diabetes. 1998 Feb;47(2):290-3
pubmed: 9519730
Diabetes Care. 2004 Jun;27(6):1349-57
pubmed: 15161787
J Clin Endocrinol Metab. 2011 Mar;96(3):766-74
pubmed: 21123448
Lancet. 1998 Sep 12;352(9131):854-65
pubmed: 9742977
Biochem J. 2007 May 1;403(3):603-13
pubmed: 17291192
Stroke. 2001 Mar;32(3):735-40
pubmed: 11239195
Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):3215-23
pubmed: 9409314
J Clin Invest. 2003 May;111(9):1373-80
pubmed: 12727929
PLoS One. 2013 Jul 02;8(7):e67748
pubmed: 23844082
Lipids Health Dis. 2012 May 15;11:55
pubmed: 22587332
Science. 2000 Sep 22;289(5487):2122-5
pubmed: 11000114
J Clin Invest. 2000 Feb;105(4):451-8
pubmed: 10683374
Endocr Rev. 2007 Aug;28(5):463-91
pubmed: 17525361
Exp Biol Med (Maywood). 2006 Jun;231(6):1044-7
pubmed: 16741046
Nat Rev Endocrinol. 2019 May;15(5):288-298
pubmed: 30814686
J Pharmacol Exp Ther. 2003 Jul;306(1):332-7
pubmed: 12684543
Circulation. 2003 Jul 1;107(25):3152-8
pubmed: 12810615
J Biol Chem. 1998 Sep 11;273(37):24266-71
pubmed: 9727051
Cardiovasc Res. 1999 Feb;41(2):465-72
pubmed: 10341846
Mol Cell Biol. 1999 May;19(5):3278-88
pubmed: 10207053
Cell Metab. 2006 Feb;3(2):87-98
pubmed: 16459310
J Biol Chem. 2001 Jul 27;276(30):27855-63
pubmed: 11285257
Arterioscler Thromb Vasc Biol. 2012 Dec;32(12):3082-94
pubmed: 23042819
Nat Rev Mol Cell Biol. 2008 Mar;9(3):193-205
pubmed: 18200017
Liver Int. 2016 Aug;36(8):1221-9
pubmed: 26901384
Mol Cell. 2000 Jul;6(1):87-97
pubmed: 10949030
Arterioscler Thromb Vasc Biol. 2004 Jun;24(6):998-1005
pubmed: 15001455
Diabetes. 1988 Dec;37(12):1595-607
pubmed: 3056758
Int J Mol Sci. 2019 Jul 04;20(13):
pubmed: 31277498
PLoS One. 2015 May 01;10(5):e0125430
pubmed: 25933289
Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13656-61
pubmed: 10570128
Mol Aspects Med. 2005 Feb-Apr;26(1-2):33-65
pubmed: 15722114
J Clin Invest. 2001 Oct;108(8):1205-13
pubmed: 11602628
Circulation. 2000 May 2;101(17):2030-3
pubmed: 10790342
Am J Physiol Heart Circ Physiol. 2005 Apr;288(4):H1770-6
pubmed: 15550522
Diabetes. 1996 Jul;45 Suppl 3:S55-8
pubmed: 8674892
Diabetes Care. 2003 Jul;26(7):2119-25
pubmed: 12832323
Dis Model Mech. 2016 Nov 1;9(11):1271-1281
pubmed: 27562101
J Clin Invest. 1999 Aug;104(4):447-57
pubmed: 10449437
N Engl J Med. 1985 Dec 19;313(25):1557-63
pubmed: 3934538
PLoS One. 2012;7(1):e30193
pubmed: 22291917