Pharmacological inhibition of c-Jun N-terminal kinase signaling prevents cardiomyopathy caused by mutation in LMNA gene.
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.
Wu
Wei
W
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Shan
Jian
J
Bonne
Gisèle
G
Worman
Howard J
HJ
Muchir
Antoine
A
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
D000873:Anthracenes; D004791:Enzyme Inhibitors; D034904:Lamin Type A; D045265:Natriuretic Peptides; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases
Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16809-13
18922779
Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13681-6
11717429
Am J Cardiol. 2000 Nov 1;86(9):1036-40, A11
11053725
Biochim Biophys Acta. 1997 Oct 24;1333(2):F85-104
9395283
Circulation. 1994 Dec;90(6):2899-904
7994836
Nat Genet. 1999 Mar;21(3):285-8
10080180
Hum Mol Genet. 2000 May 22;9(9):1453-9
10814726
J Clin Invest. 2007 May;117(5):1282-93
17446932
Cell Mol Life Sci. 1999 Aug 15;55(10):1230-54
10487205
Nephrol Dial Transplant. 2000;15 Suppl 6:66-8
11143996
N Engl J Med. 1999 Dec 2;341(23):1715-24
10580070
Physiology (Bethesda). 2004 Oct;19:309-14
15381760
Circulation. 1987 Jul;76(1):44-51
3594774
N Engl J Med. 2006 Jan 12;354(2):209-10
16407522
Eur J Heart Fail. 2003 Dec;5(6):717-23
14675849
Recent Pat Anticancer Drug Discov. 2009 Jan;4(1):28-35
19149686
J Clin Invest. 2001 Jul;108(1):73-81
11435459
Hum Mol Genet. 2009 Jan 15;18(2):241-7
18927124
Exp Biol Med (Maywood). 2002 May;227(5):301-14
11976400
Hum Mol Genet. 2005 Jan 1;14(1):155-69
15548545