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.
Highlights
Heart failure is a leading cause of death worldwide
While Pressure overload (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 left ventricular (LV) remodeling
Peripheral insulin resistance is a common characteristic of heart failure and type 2 diabetes (T2D) that results in initial compensatory hyperinsulinemia and increased proximal myocardial insulin signaling [2, 3]
Summary
The associated prognosis is worse than prognoses for many malignancies, with about half of patients dying within 5 years of the initial diagnosis [1]. Peripheral insulin resistance is a common characteristic of heart failure and type 2 diabetes (T2D) that results in initial compensatory hyperinsulinemia and increased proximal myocardial insulin signaling [2, 3]. Numerous epidemiologic studies indicate that insulin resistance and diabetes are risk factors for heart failure, of ischemic and nonischemic origins [3]. Patients with T2D are commonly treated with insulin in later stages of the disease, and hyperinsulinemia has been associated with impaired myocardial contractile function in humans and animal studies [4, 5].
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call