@article{10.1172/jci.insight.134920, author = {Christian Riehle AND Eric T. Weatherford AND Adam R. Wende AND Bharat P. Jaishy AND Alec W. Seei AND Nicholas S. McCarty AND Monika Rech AND Qian Shi AND Gopireddy R. Reddy AND William J. Kutschke AND Karen Oliveira AND Karla Maria Pires AND Joshua C. Anderson AND Nikolaos A. Diakos AND Robert M. Weiss AND Morris F. White AND Stavros G. Drakos AND Yang K. Xiang AND E. Dale Abel}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling}, year = {2020}, month = {3}, volume = {5}, url = {https://insight.jci.org/articles/view/134920}, 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.}, number = {6}, doi = {10.1172/jci.insight.134920}, url = {https://doi.org/10.1172/jci.insight.134920}, }