Insulin receptor substrates differentially exacerbate insulin-mediated left
ventricular remodeling.
Authors Riehle C, Weatherford ET, Wende AR, Jaishy BP, Seei AW, McCarty NS, Rech M, Shi
Q, Reddy GR, Kutschke WJ, Oliveira K, Pires KM, Anderson JC, Diakos NA, Weiss
RM, White MF, Drakos SG, Xiang YK, Abel ED
Submitted By Submitted Externally on 4/28/2020
Status Published
Journal JCI insight
Year 2020
Date Published 3/1/2020
Volume : Pages 5 : Not Specified
PubMed Reference 32213702
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.