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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 5

Increased cGMP/PKG signaling in CIRS1KO hearts.

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Increased cGMP/PKG signaling in CIRS1KO hearts.
(A and B) Two-step netwo...
(A and B) Two-step network for TAC regulated kinase pathways in WT and CIRS1KO hearts relative to Sham controls (n = 6). The proteins from which the phosphosubstrates were derived were uploaded to GeneGo MetaCore (portal.genego.com) for network modeling. A Djikstras Shortest Paths algorithm allowing 1-step connections between uploaded kinases was used to generate the network for TAC altered kinases. Blue circles indicate increased nodes. No significantly regulated upstream kinase activation was identified for CIRS2KO hearts after TAC surgery. 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, $P < 0.05 for genotype, and &P < 0.05 for the interaction between TAC surgery and genotype. (C and D) mRNA expression of Nppa (#,$,&) and Nppb (#,&) normalized to Rps16 4 weeks after surgery, n = 8. (E and F) cGMP levels (n = 7–10; #,$) and PKG activity (n = 7–10; #,$) presented as a fold change relative to WT Sham. *P < 0.05 vs. WT same surgery, †P < 0.05 vs. Sham same genotype, ‡P < 0.05 vs. CIRS1KO same surgery. (G) ANP stimulated cGMP production in cardiomyocytes obtained from IRS1lox/lox and CIRS1KO mice measured by using the FRET-based cGMP sensor cGi-500 with or without varying concentrations of the PDE9a-specific inhibitor PF-04447943. n = 3–5 mice, n = 12–31 cells/group total analyzed. Two-way ANOVA analysis was performed (P < 0.05 for genotype, treatment, and interaction between genotype and treatment) followed by Holm-Šídák post hoc analysis; *P < 0.05 vs. IRS1lox/lox same PF-04447943 concentration. (H) Proposed model for increased NP/cGMP/PKG signaling in CIRS1KO hearts. Changes in CIRS1KO hearts are presented relative to WT controls.

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