Abstract 3941: Oxidative Stress Mediates Cardiac Hypertrophy and Myocardial Insulin Resistance in the UCP-DTA Mouse Model of the Metabolic Syndrome
Insulin resistance (IR) and oxidative stress may contribute to cardiac dysfunction in obesity-related disorders such as the metabolic syndrome (MS) and type 2 diabetes. To determine the contribution of oxidative stress to cardiac dysfunction and IR, 20 week-old UCP-DTA (UD) mice, a rodent model of the MS and obesity, and wildtype littermates (WT) were treated with the SOD2 mimetic, MnTBAP (20mg/kg/day) or saline for 4 weeks. At 24 weeks, saline and MnTBAP treated UD mice remained glucose intolerant and had a 50% increase in body mass vs. WT (p<0.0001). Heart weight/tibia length ratios (HW/TL) were 35% higher in UD mice vs. WT (p<0.0001), and reduced to 27% (p<0.03) with MnTBAP, which did not alter HW in WT mice. Cardiomyocyte cross-sectional area was increased in UD mice and was normalized by MnTBAP. NDUFA9 protein (subunit of mitochondrial complex1) was reduced by 54% (p<0.05) in UD mice with no change in NDUFA9 mRNA and MnTBAP restored NDUFA9 protein levels in UD mice. MnTBAP increased mitochondrial aconitase activity by 40% (p<0.05) and lowered H2O2 production in isolated mitochondria from UD hearts. ADP-stimulated oxygen consumption with palmitoyl-carnitine was decreased in saponin-permeabilized cardiac fibers from UD hearts vs. WT (−17%, p<0.05), and was normalized by MnTBAP. Ex vivo glucose oxidation rates (GOR) and cardiac function were assessed in isolated working hearts perfused with 5mM glucose and 0.4mM palmitate. GOR of saline-treated UD mouse hearts did not respond to 1nM insulin (217.5±42.7 vs. 262.6±51.9 nmol/min/gdhw, p>0.6), but MnTBAP restored insulin-mediated stimulation of GOR in UD mouse hearts (290.8±36.2 vs. 584.7±84.2, basal versus insulin, p<0.001). Insulin-mediated phosphorylation of Akt and GSK3 were normal in UD mice, indicating that Akt-independent pathways mediate insulin resistance in UD hearts. Cardiac power was reduced in UD mice vs. WT (20.06±1.3 vs. 24.3±1.1mWatt/gdhw, p<0.04), and did not improve with short term MnTBAP. Thus inhibition of mitochondrial ROS production in obesity improves mitochondrial function, attenuates cardiac hypertrophy and restores myocardial insulin sensitivity without changing body mass, glucose tolerance, or body lipid composition.