title: Pharmacological inhibition of c-Jun N-terminal kinase signaling prevents cardiomyopathy caused by mutation in LMNA gene.
abstract: 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 JNK activation in the development of cardiomyopathy caused by LMNA mutations. They further provide proof-of-principle for JNK inhibition as a novel therapeutic option to prevent or delay the cardiomyopathy in humans with mutations in LMNA.
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Jian
authors.initials: J
authors.lastname: Shan
authors.forename: Gisèle
authors.initials: G
authors.lastname: Bonne
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Worman
authors.forename: Antoine
authors.initials: A
authors.lastname: Muchir
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics / Q000502:physiology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology / Q000627:therapeutic use*; D009202:Cardiomyopathies / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D034904:Lamin Type A / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D045265:Natriuretic Peptides / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000873:Anthracenes; D004791:Enzyme Inhibitors; D034904:Lamin Type A; D045265:Natriuretic Peptides; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases
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