Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1802, Issue 7-8, Pages 632-638Publisher
ELSEVIER
DOI: 10.1016/j.bbadis.2010.04.001
Keywords
Cardiomyopathy; Lamin; MAP kinase; JNK; Emery-Dreifuss muscular dystrophy
Funding
- National Institutes of Health [AR048997]
- Muscular Dystrophy Association [MDA4287]
Ask authors/readers for more resources
Mutations in LMNA, which encodes A-type nuclear lamins, cause disorders of striated muscle that have as a common feature dilated cardiomyopathy. We have demonstrated an abnormal activation of both the extracellular signal-regulated kinase (ERK) and the c-Jun N-terminal kinase (JNK) branches of the mitogen-activated protein kinase signaling cascade in hearts from Lmna(H222P/H222P) mice that develop dilated cardiomyopathy. We previously showed that pharmacological inhibition of cardiac ERK signaling in these mice delayed the development of left ventricle dilatation and deterioration in ejection fraction. In the present study, we treated Lmna(H222P/H222P) mice with SP600125, an inhibitor of JNK signalling. Systemic treatment with SP600125 inhibited JNK phosphorylation, with no detectable effect on ERK. It also blocked increased expression of RNAs encoding natriuretic peptide precursors and proteins involved in the architecture of the sarcomere that occurred in placebo-treated mice. Furthermore, treatment with SP600125 significantly delayed the development of left ventricular dilatation and prevented decreases in cardiac ejection fraction and fibrosis. These results demonstrate a role for INK activation in the development of cardiomyopathy caused by LMNA mutations. They further provide proof-of-principle for INK inhibition as a novel therapeutic option to prevent or delay the cardiomyopathy in humans with mutations in LMNA. (C) 2010 Elsevier B.V. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available