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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 4

Isoform-specific hyperactivation of IRS1-Akt1 signaling in human heart failure.

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Isoform-specific hyperactivation of IRS1-Akt1 signaling in human heart f...
(A and B) Representative immunoblot and densitometric analysis of protein levels. (C) Tyrosine phosphorylation of IRS proteins measured by ELISA and normalized to protein abundance in human heart failure samples (n = 14–16) and nonfailing controls (n = 6–7). (D and E) Representative immunoblots and immunoprecipitations in homogenates from human heart failure samples and nonfailing controls and densitometric quantification of immunoblots as indicated. (F and G) P-Akt Ser473 following Akt1 immunoprecipitation normalized to total Akt1 protein and P-Akt Ser473 following Akt2 immunoprecipitation normalized to total Akt2 protein. Lanes were run on the same gel but were noncontiguous. Data shown are mean values ± SEM presented as a fold change relative to nonfailing controls, n = 7–15. *P < 0.05 vs. nonfailing controls. (H) Schematic summary of signaling changes in human heart failure samples and murine WT hearts after TAC relative to nonfailing controls or WT Sham controls, respectively. Note that IRS1 is hyperphosphorylated in both WT mice after TAC and human heart failure samples. IRS1 total protein abundance is also increased in WT mice after TAC. (I and J) Summary of changes in CIRS1KO and CIRS2KO × Akt1het hearts after TAC relative to TAC operated WT controls.
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