Journal
HUMAN MOLECULAR GENETICS
Volume 21, Issue 19, Pages 4325-4333Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/dds265
Keywords
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Funding
- NIH/NIHMS [R01AR048997]
- Muscular Dystrophy Association [MDA172222]
- Association Francaise Contre les Myopathies
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We previously interrogated the transcriptome in heart tissue from Lmna(H222P/H222P) mice, a mouse model of cardiomyopathy caused by lamin A/C gene (LMNA) mutation, and found that the extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase branches of the mitogen-activated protein (MAP) kinase signaling pathway were abnormally hyperactivated prior to the onset of significant cardiac impairment. We have now used an alternative gene expression analysis tool to reanalyze this transcriptome and identify hyperactivation of a third branch of the MAP kinase cascade, p38 signaling. Biochemical analysis of hearts from Lmna(H222P/H222P) mice showed enhanced p38 activation prior to and after the onset of heart disease as well as in hearts from human subjects with cardiomyopathy caused by LMNA mutations. Treatment of Lmna(H222P/H222P) mice with the p38 inhibitor ARRY-371797 prevented left ventricular dilatation and deterioration of fractional shortening compared with placebo-treated mice but did not block the expression of collagen genes involved in cardiac fibrosis. These results demonstrate that three different branches of the MAP kinase signaling pathway with overlapping consequences are involved in the pathogenesis of cardiomyopathy caused by LMNA mutations. They further suggest that pharmacological inhibition of p38 may be useful in the treatment of this disease.
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