Abstract 13124: Manganese Superoxide Dismutase Deficient Mice Show Diastolic Dysfunction
Background: Previously, we demonstrated that the depletion of NO bioavailability caused by increased reactive oxygen species (ROS) induced diastolic dysfunction with preserved systolic function through nitric oxide synthase (NOS) uncoupling in the heart. Depletion of tetrahydrobiopterin (BH4) causes NOS uncoupling, resulting in relaxation impairment of the heart. Mitochondria are one of the major cardiac oxidative stress sources, and manganese superoxide dismutase (MnSOD) is a mitochondrial antioxidant enzyme. In the present study, we sought to determine whether heterozygous knockout of the MnSOD gene (Sod2 +/-) would be associated with diastolic dysfunction (DD) that could be ameliorated by BH4.
Methods: Echocardiography was used to determine DD in heterozygous MnSOD knockout mice. The mitral annulus longitudinal velocities (E’, and A’) were determined by pulsed-wave tissue Doppler from the apical four-chamber view. Mitochondrial ROS were measured by confocal microscopy and flow cytometry from isolated cardiomyocytes using MitoSOX Red. NO was measured by DAF-FM and by the Griess reaction. Contraction and relaxation impairment were assessed by IonOptix System.
Results: Mitochondrial ROS were elevated by 2.6-fold and NO level was reduced by 0.77-fold in cardiomyocytes from MnSOD deficient mice. The ratio of mitral annulus longitudinal velocities (E’/A’) were significantly reduced indicating DD at MnSOD deficient mice (MnSOD 0.88 ± 0.14 vs. WT 1.11 ± 0.11). Resting sarcomere length was significantly reduced in MnSOD deficient cardiomyocytes compared to WT (MnSOD 1.68 ± 0.01 µm vs. WT 1.84 ± 0.01 µm, P<0.001) and the relaxation constant (tau) was significantly increased (MnSOD 0.12 ± 0.01 vs. WT 0.09 ±0.01, P<0.05). BH4 treatment improved resting sarcomere length (1.77 ±0.01 µm, P<0.001) and tau (0.73 ±0.01, P<0.001) compared to MnSOD.
Conclusions: MnSOD deficiency was associated impaired cardiac relaxation indicating DD, which could be improved with BH4 treatment.
- © 2011 by American Heart Association, Inc.