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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 3

Heterozygous deletion of Akt1 prevents hyperactivation of the mTOR signaling pathway and protects against heart failure in IRS2-deficient hearts 4 weeks after TAC.

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Heterozygous deletion of Akt1 prevents hyperactivation of the mTOR signa...
Two-way ANOVA was performed to analyze differences 4 weeks after TAC surgery and 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, $P < 0.05 for genotype, and &P < 0.05 for the interaction between TAC surgery and genotype. (A and B) Representative photographs and H&E stains of longitudinal sections 4 weeks after surgery as indicated. Scale bars: 2 mm. (C) Heart weights normalized to tibia length (n = 10; #,$,&). (D–K) In vivo contractile function and hemodynamic parameters as determined by ejection fraction (#,&) (D), left ventricular cavity diameter at systole (LVDs, #,$,&) (E), maximum rates of increase (Max, #,$) (F) and decrease (Min, #,$,&) (G) in left ventricular pressure [dP/dt], wet lung weights normalized to tibia length (n = 10; #,$) (H), and mRNA expression of Acta1, Nppa, and Nppb (I–K) (#,$,& each) normalized to Cphn 4 weeks after surgery, n = 8. (L–R) Representative immunoblots in ventricle homogenates 4 weeks after TAC surgery and densitometric quantification as indicated (presented as a fold change relative to Sham surgery same genotype; n = 6–9). Data shown are mean values ± SEM. *P < 0.05 vs. Sham same genotype, †P < 0.05 vs. Akt1 WT same surgery, ‡P < 0.05 vs. IRS2 WT same surgery.
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