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Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling.

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.

SUBMITTER: Riehle C

PROVIDER: S-EPMC7213803 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling.

Riehle Christian C Weatherford Eric T ET Wende Adam R AR Jaishy Bharat P BP Seei Alec W AW McCarty Nicholas S NS Rech Monika M Shi Qian Q Reddy Gopireddy R GR Kutschke William J WJ Oliveira Karen K Pires Karla Maria KM Anderson Joshua C JC Diakos Nikolaos A NA Weiss Robert M RM White Morris F MF Drakos Stavros G SG Xiang Yang K YK Abel E Dale ED

JCI insight 20200326 6

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 (CI ...[more]

PMID: 32213702

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Project description:Background and objectivesHigher left ventricular volume is associated with death in patients with ESRD. This work investigated the effects of frequent hemodialysis on ventricular volumes and left ventricular remodeling.Design, setting, participants, & measurementsThe Frequent Hemodialysis Network daily trial randomized 245 patients to 12 months of six times per week versus three times per week in-center hemodialysis; the Frequent Hemodialysis Network nocturnal trial randomized 87 patients to 12 months of six times per week nocturnal hemodialysis versus three times per week predominantly home-based hemodialysis. Left and right ventricular end systolic and diastolic volumes, left ventricular mass, and ejection fraction at baseline and end of the study were ascertained by cardiac magnetic resonance imaging. The ratio of left ventricular mass/left ventricular end diastolic volume was used as a surrogate marker of left ventricular remodeling. In each trial, the effect of frequent dialysis on left or right ventricular end diastolic volume was tested between predefined subgroups.ResultsIn the daily trial, frequent hemodialysis resulted in significant reductions in left ventricular end diastolic volume (-11.0% [95% confidence interval, -16.1% to -5.5%]), left ventricular end systolic volume (-14.8% [-22.7% to -6.2%]), right ventricular end diastolic volume (-11.6% [-19.0% to -3.6%]), and a trend for right ventricular end systolic volume (-11.3% [-21.4% to 0.1%]) compared with conventional therapy. The magnitude of reduction in left and right ventricular end diastolic volumes with frequent hemodialysis was accentuated among patients with residual urine output<100 ml/d (P value [interaction]=0.02). In the nocturnal trial, there were no significant changes in left or right ventricular volumes. The frequent dialysis interventions had no substantial effect on the ratio of left ventricular mass/left ventricular end diastolic volume in either trial.ConclusionsFrequent in-center hemodialysis reduces left and right ventricular end systolic and diastolic ventricular volumes as well as left ventricular mass, but it does not affect left ventricular remodeling.

Dataset Information

Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling.

Publications

Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling.

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