Abstract 15864: Whole Body Periodic Acceleration (pGz); A Novel Therapeutic Approach in Dystrophin -/- Utrophin-/- (DKO) Cardiomyopathy
Duchenne Muscular Dystrophy cardiomyopathy (DMDC) is a progressive lethal disease. The dystrophin and utrophin double knock-out (DKO) mice (dystrophin–/–/utrophin–/–) share histopathological markers with DMDC. DKO is a very severe model of DMDC. pGz is the sinusoidal head to foot motion of the body, inducing pulsatile shear stress to the vascular endothelium activating endothelial nitric oxide synthase (eNOS) to produce small quantities of cardiac eNO. eNO has been shown to reduce ROS production, modulate intracellular Ca2+ and Na+ concentrations and inhibit calpain mediated proteolysis. We previously showed that pGz decreases diastolic Ca2+ and Na+ overload in cardiomyocytes from mdx mice, and confers cardioprotection.
Hypothesis: We tested the hypothesis that pGz may also confer cardioprotection in the most severe form of DMDC, the DKO.
Methods: DKO mice were randomized at 3-mo of age to daily pGz (ƒ=480 cpm,Gz ± 3.0 mt/sec2,1hr/day for 2 weeks) (DKO+pGz) or none (DKO), a separate age matched non-diseased group of wt (CONT) and CONT treated with pGz (CONT+pGz). Cardiomyocytes where isolated from each group and intracellular diastolic Ca2+ ([Ca2+]d) and Na+ ([Na+]d) measured with microelectrodes. Calpain activity (Calpain-Glo), ROS production (DCFH-DA), were also measured.
Results: DKO mice had a 5X and 4X fold(X) elevation in [Ca2+]d and [Na+]d, respectively compared to CONT. pGz significantly reduced this elevation. Calpain activity was significantly increased (3X) in DKO compared to CONT and it was reduced by pGz. ROS production which was increased in DKO (3X) was blunted by pGz. pGz did not affect [Ca2+]d, [Na+]d, Calpain activity or ROS production in CONT. [(Figure, M±SD )***p< 0.001]
Conclusion: pGz markedly improves intracellular Ca2+ and Na+ as well as decreasing Calpain and ROS production in DKO cardiomyocytes. These finding suggest that pGz has therapeutic potential as a novel therapeutic intervention in DMD cardiomyopathy.
Author Disclosures: A. Mijares: None. J. Kolster: None. J.A. Adams: Ownership Interest; Modest; Stock options totaling < $10,000. J.R. Lopez: None.
- © 2015 by American Heart Association, Inc.