Abstract 14229: Isoform-Specific Modulation of Left Ventricular Remodeling by Insulin Receptor Substrates (IRS) in Response to Pressure Overload
Pressure overload hypertrophy (POH)-induced heart failure leads to generalized insulin resistance. The associated hyperinsulinemia increases cardiomyocyte insulin receptor signaling leading to augmented phosphorylation of insulin receptor substrate (IRS) 1 and Akt, which accelerates left ventricular (LV) remodeling. This study tested the hypothesis that IRS1 but not IRS2 mediates POH-induced LV remodeling. Cardiomyocyte-specific knockouts for IRS1 (CIRS1KO) or IRS2 (CIRS2KO) were subjected to transverse aortic constriction (TAC). In non-stressed hearts, IRS1-deficient hearts were reduced in size with heart weight/tibia length ratio, HW/TL, reduced by 14.5%, whereas IRS2-deficient hearts exhibited baseline cardiac hypertrophy (HW/TL increased by 6.3%), p<0.05 each. Relative to sham operated mice, 4 weeks of TAC, induced LV hypertrophy in WT hearts (HW/TL +54.4%) but the hypertrophic response was attenuated in IRS1-deficient hearts (+18.6%), p<0.05 each. In contrast, the hypertrophic response was amplified in IRS2-deficient hearts (+67.4%, p<0.05). Maximal dP/dt (by LV catheterization in vivo) following TAC was decreased by 19.3%, in WT hearts (p<0.05), but was unchanged relative to sham in TAC operated CIRS1KO hearts. However, dP/dt was impaired to a greater extent by TAC in CIRS2KO hearts (-38.2%, p<0.05). Similarly, wet lung weights normalized to tibia length ratio were only increased in CIRS2KO following TAC (+38.4% vs. CIRS2KO Sham, p<0.05) indicating pulmonary edema. Phosphorylation of Akt (Thr308) and S6 were increased in WT and CIRS2KO hearts following TAC by 1.55-fold and 2.14-fold, respectively (p<0.05) while no increase was observed in CIRS1KO hearts following TAC. These data suggest that IRS1 but not IRS2 signaling mediates the Akt - driven acceleration of LV remodeling that accompanies POH, and that reducing IRS1 signaling or preserving IRS2 signaling is cardioprotective in POH.
- © 2012 by American Heart Association, Inc.