Abstract 1822: Epigenetic Parallelism Between Hindlimb Ischemia And Duchenne Muscular Dystrophy Revealed By Global Histone Modification Profiling
INTRODUCTION & BACKGROUND: Recent studies indicate that in the MDX mouse model of Duchenne muscle dystrophy (DMD) nitric oxide (NO) production is significantly compromised leading to skeletal muscle, vascular and cardiac alterations. We recently reported that in normal endothelial cells NO regulates chromatin remodelling and gene expression via histone deacetylases (HDAC) activation and function. The role of epigenetics in the onset of DMD-associated vascular dysfunction was examined in a series of experiments aimed at identifying histone tail modifications and gene expression in freshly isolated MDX pulmonary endothelial cells (PEC) and adductor muscle.
METHODS & RESULTS: PECs were obtained from normal c57BL-J10 and MDX mice and kept in static (ST) culture or exposed to a laminar shear stress (SS) of 10 dyne/cm2 for 8 to 16 hours to evaluate NO production. In this condition, PECs isolated from MDX mice revealed a markedly lower NO production compared to normal controls. This observation prompted us to evaluate the global pattern of histone H3 modification and found that several changes could be detected in PECs from MDX including high levels of acetylated Lysine 14, methylated Lysine 4 and 79, and phosphorylated Serine 10. These modifications remained elevated upon SS treatment and were reverted by NO donors treatment. In vivo, similar global histone modifications were found in regenerating MDX skeletal muscle fibres and vascular structures and in normal mice at 3, 7, and 14 days after hind-limb ischemia underlying the presence of a common epigenetic mechanism between these pathological conditions. Remarkably, prolonged L-NAME treatment of normal mice induced the same epigenetic modification pattern detected in dystrophic and ischemic hind-limbs further suggesting a role for NO in the pathogenesis of aberrant chromatin remodelling profiles.
CONCLUSION: a NO-dependent altered chromatin landscape characterizes MDX endothelial cells and skeletal muscle which is reproduced in regenerating post-ischemic adductor muscle suggesting that common molecular mechanisms underly muscular dystrophy and acute hind-limb ischemia.