Abstract 15650: Insulin Signaling Mediates the Induction of Glycolysis and the Activation of Anti-Oxidant Defenses Following Pressure Overload-Induced Cardiac Hypertrophy
Absence of insulin signaling in cardiomyocytes is associated with mitochondrial dysfunction in non-stressed hearts and exacerbates pressure overload-induced contractile dysfunction and pathological remodeling. It is not known if additional impairment of mitochondrial function is responsible for exacerbating LV dysfunction in this model following transverse aortic constriction (TAC). Mice with cardiac-specific insulin receptor knockout (CIRKO) and their wild type littermate controls (Cont) were subjected to TAC or sham surgery. Four weeks after TAC, contractile function, cardiac metabolism, and mitochondrial function were assessed (n=6 mice/group). Following TAC, pressure overload-induced contractile dysfunction was exacerbated in CIRKO mice, as demonstrated by reduced fractional shortening and +dP/dt relative to Cont mice. Cardiac fibrosis was also intensified in CIRKO mice versus Cont after TAC. 4-HNE staining was used as an index of oxidative stress. In Cont mice, banding increased 4-HNE by 1.64 above Cont sham. In CIRKO mice, 4-HNE staining after TAC was increased by 2.14 fold relative to Cont sham (p<0.05). Of note, whereas TAC induced a 3-fold increase of mitochondrial superoxide dismutase (Sod2) protein in Cont mice, there was no induction of Sod2 protein in CIRKO hearts after TAC. In isolated working hearts, TAC increased glycolysis by 2-fold in Cont mice relative to Cont sham (p<0.05). In contrast, glycolysis rates decreased in CIRKO mice by 33% after TAC (p<0.05) relative to sham CIRKO. Palmitate oxidation was equivalently reduced in all groups relative to Cont sham mice. CIRKO mice exhibited mitochondrial dysfunction at baseline, which is not worsened by TAC. In contrast, mitochondrial function declined in Cont TAC mice relative to Cont Sham. Thus, progressive mitochondrial dysfunction is not the mechanism for heart failure following TAC in insulin-receptor deficient hearts. Rather, our studies reveal a novel role for insulin signaling in mediating anti-oxidant defenses in the context of pressure overload.
- © 2013 by American Heart Association, Inc.