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Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling
Christian Riehle, … , Yang K. Xiang, E. Dale Abel
Christian Riehle, … , Yang K. Xiang, E. Dale Abel
Published March 26, 2020
Citation Information: JCI Insight. 2020;5(6):e134920. https://doi.org/10.1172/jci.insight.134920.
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Research Article Cardiology

Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling

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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.

Authors

Christian Riehle, Eric T. Weatherford, Adam R. Wende, Bharat P. Jaishy, Alec W. Seei, Nicholas S. McCarty, Monika Rech, Qian Shi, Gopireddy R. Reddy, William J. Kutschke, Karen Oliveira, Karla Maria Pires, Joshua C. Anderson, Nikolaos A. Diakos, Robert M. Weiss, Morris F. White, Stavros G. Drakos, Yang K. Xiang, E. Dale Abel

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Figure 2

Deletion of IRS1 prevents hyperactivation of Akt1/mTOR signaling in response to pressure overload 4 weeks after TAC.

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Deletion of IRS1 prevents hyperactivation of Akt1/mTOR signaling in resp...
Two-way ANOVA was performed to analyze differences 4 weeks after TAC surgery by genotype, followed by Holm-Šídák post hoc analysis. Results of post hoc analyses for each comparison are summarized by symbols as defined: #P < 0.05 for TAC surgery, $P < 0.05 for genotype, and &P < 0.05 for the interaction between TAC surgery and genotype. (A–H) Representative immunoblots in ventricle homogenates of WT, CIRS1KO, and CIRS2KO mice post-TAC surgery (A) and densitometric quantification of P-Akt Ser473/Total Akt (#) (B), P-Akt Thr308/Total Akt (#,&) (C),P-FoxO3a Ser318/321/Total FoxO3 (#,$,&) (D), P-mTOR Ser2448/Total mTOR (#,$) (E), P-S6 Ser 235/236/Total S6 ($) (F),P-4E-BP1 Thr37/46 γ form/GAPDH ($,&) (G), and 4E-BP1 γ form/GAPDH (#,&) (H); n = 4–8 each. (I–M) Representative immunoblots following immunoprecipitation for Akt1 or Akt2 (I) and densitometric quantification of P-Akt Ser473/Akt1 (#,$,&) (J), P-Akt Thr308/Akt1 (#,$,&) following immunoprecipitation for Akt1 (K), P-Akt Ser473/Akt2 (&) (L), and P-Akt Thr308/Akt2 ($,&) (M) following immunoprecipitation for Akt2 as indicated; n = 4 each. Data shown are mean values ± SEM. *P < 0.05 vs. WT same surgery, †P < 0.05 vs. Sham same genotype, ‡P < 0.05 vs. CIRS1KO same surgery.

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