Abstract 15685: Inhibition of Site Specific Phosphorylation of Retinoblastoma Protein by a p38 Inhibitor Decreases Apoptosis, Improves Survival and Prevents Cardiomyopathy Caused by a Mutation in LMNA gene.

Background: Mutations in LMNA gene are associated with a wide range of diseases known as laminopathies in which dilated cardiomyopathy (DCM) is a common finding. One such laminopathy is modelled in mice by a missense mutation (N195K) resulting in DCM and sudden death by 6-7 weeks of age. An abnormal activation of the p38 branch of the mitogen-activated protein kinase (MAPK) signalling cascade was seen in hearts of LmnaN195K mice. Methods & Results: We treated LmnaN195K mice that develop cardiomyopathy with ARRY-371797, an inhibitor of p38 activation. Serial echocardiographic measurements revealed a significant increase in ejection fraction, fractional shortening and a significant decrease in left ventricular end diastolic diameter in treated vs. untreated mutants. Electron microscopy demonstrated preservation of cellular and nuclear architecture in treated vs. untreated mutants where alteration in nuclear shape and disarray in cellular architecture was apparent. Treated N195K mice also showed an increase ...