Journal article
Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling
JCI insight, Vol.5(6), e134920
03/26/2020
DOI: 10.1172/jci.insight.134920
PMCID: PMC7213803
PMID: 32213702
Abstract
Pressure overload (PO) cardiac hypertrophy and heart failure are associated with generalized insulin resistance and hyperinsulinemia, which may exacerbate left ventricular (LV) remodeling. While PO activates insulin receptor tyrosine kinase activity that is transduced by insulin receptor substrate 1 (IRS1), the present study tested the hypothesis that IRS1 and IRS2 have divergent effects on PO-induced LV remodeling. We therefore subjected mice with cardiomyocyte-restricted deficiency of IRS1 (CIRS1KO) or IRS2 (CIRS2KO) to PO induced by transverse aortic constriction (TAC). In WT mice, TAC-induced LV hypertrophy was associated with hyperactivation of IRS1 and Akt1, but not IRS2 and Akt2. CIRS1KO hearts were resistant to cardiac hypertrophy and heart failure in concert with attenuated Akt1 activation. In contrast, CIRS2KO hearts following TAC developed more severe LV dysfunction than WT controls, and this was prevented by haploinsufficiency of Akt1. Failing human hearts exhibited isoform-specific IRS1 and Akt1 activation, while IRS2 and Akt2 activation were unchanged. Kinomic profiling identified IRS1 as a potential regulator of cardioprotective protein kinase G–mediated signaling. In addition, gene expression profiling revealed that IRS1 signaling may promote a proinflammatory response following PO. Together, these data identify IRS1 and Akt1 as critical signaling nodes that mediate LV remodeling in both mice and humans.
Insulin receptor substrate (IRS) 1 and Akt1 are critical signaling nodes that mediate left ventricular remodeling in both mice and humans.
Details
- Title: Subtitle
- Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling
- Creators
- Christian Riehle - University of IowaEric T. Weatherford - University of IowaAdam R. Wende - University of Alabama at BirminghamBharat P. Jaishy - University of IowaAlec W. Seei - University of IowaNicholas S. McCarty - University of IowaMonika Rech - University of UtahQian Shi - University of IowaGopireddy R. Reddy - University of California, DavisWilliam J. Kutschke - University of IowaKaren Oliveira - University of UtahKarla Maria Pires - University of UtahJoshua C. Anderson - University of Alabama at BirminghamNikolaos A. Diakos - University of UtahRobert M. Weiss - University of IowaMorris F. White - Boston Children's HospitalStavros G. Drakos - University of UtahYang K. Xiang - University of California, DavisE. Dale Abel - University of Iowa
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.5(6), e134920
- DOI
- 10.1172/jci.insight.134920
- PMID
- 32213702
- PMCID
- PMC7213803
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- American Society for Clinical Investigation
- Grant note
- RI 2417/1-1 / ; Research fellowship to KMP / ; R01DK092065,R01HL070070,R01HL108379,U01HL087947,R01HL127764,R01HL112413,R01DK098655,R01HL135121-01,R01HL132067,OD019941,5T32HL007638,K99 HL111322,R01HL133011 / ; TFG-001 / Nora Eccles Treadwell Foundation Research fellowship to MR / Maastricht University HF 16SFRN29020000 / ; 10-2009-672 / ; Research fellowship to MR / Netherlands Heart Foundation (NHF)
- Language
- English
- Date published
- 03/26/2020
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359564402771
Metrics
17 Record Views