Abstract 4826: Nitric Oxide Synthase 3 Predisposes to Adverse Left Ventricular Remodeling in Insulin Resistance
Insulin resistance frequently clusters with disorders characterized by left ventricular (LV) pressure-overload such as systemic hypertension. We previously observed that feeding mice a high fat diet (HFD) induced insulin resistance and increased adverse LV remodeling and mortality after transverse aortic constriction (TAC). The aim of our study was to investigate the role of NOS3 in predisposing HFD-fed mice to adverse LV remodeling induced by pressure-overload. C57BL6 wild type mice (WT, n=20), mice with cardiomyocyte-specific NOS3 overexpression (NOS3TG, n=12), and NOS3-deficient mice (NOS3−/−, n=13) were fed a HFD. After 9d of HFD, mice underwent TAC. LV structure and function were followed using echo before, 7, 21 and 28 days after TAC. The LV was weighted at 28d. Reactive oxygen species (ROS) production was measured by lucigenin-enhanced chemiluminescence 7 days after TAC in a subgroup of 15 WT, 7 NOS3TG and 3 NOS3−/− mice. Before TAC, no difference in LV structure and function was seen between the 3 genotypes. TAC induced LV hypertrophy in all mice. LV/body mass ratio at 28 days was greater in WT and NOS3TG (4.9±0.3 and 5.6±0.4 mg/g, respectively) than in NOS3−/− (3.6±0.1 mg/g, p<0.05 for both). Serial echos revealed concentric LV hypertrophy in NOS3−/− and WT mice. 28 days after TAC, posterior wall thickness was greater in WT than in NOS3−/− mice (1.3±0.05 vs 1.1±0.03 mm, respectively, p<0.05), and LV fractional shortening (FS) was less (47±4 vs 54±2%, p<0.05). In contrast, NOS3TG mice developed eccentric hypertrophy: LV diastolic internal diameter was greater in NOS3TG than in WT mice (3.8±0.2 vs 3.2±0.2 mm) associated with a marked decrease in FS (27±4%, p<0.05 vs. WT). Survival 28 days after TAC was less in NOS3TG and WT (41 and 50%, respectively) than in NOS3−/− mice (100% survival, p<0.05). Cardiac tissue ROS production was similar in WT and NOS3−/− (33±5 vs 37±37 cpm/mg, p=0.4) but was greater in NOS3TG (130±7 cpm/mg, p=0.03 vs WT). In mice with insulin resistance induced by a HFD, NOS3 deficiency decreased adverse LV remodeling and mortality after pressure overload. Whereas NOS3 overexpression and increased ROS production were associated with LV remodeling and dysfunction, no association was found with mortality, suggesting alternative mechanisms.