Human Molecular Genetics Advance Access published online on October 16, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn343
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Inhibition of extracellular signal-regulated kinase signaling to prevent cardiomyopathy caused by mutation in the gene encoding A-type lamins
1 Department of Medicine, Columbia University, New York, NY, USA 2 Department of Pathology and Cell Biology, Columbia University, New York, NY, USA 3 Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA 4 Clyde and Helen Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, NY, USA 5 Institut National de la Santé et de la Recherche Médicale, U582, Institut de Myologie, Paris, France 6 Université Pierre et Marie Curie-Paris 6, Faculté de Médecine, Paris, France 7 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, U. F. Myogénétique et Cardiogénétique, Service de Biochimie Métabolique, Paris, France
* Correspondence: Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, 10th Floor, Room 508, New York, NY 10032, USA; Phone: 212-305-8156, Fax: 212-305-6443, Email: hjw14{at}columbia.edu.
Received September 22, 2008; Revised October 14, 2008; Accepted October 14, 2008
Autosomal Emery-Dreifuss muscular dystrophy and related disorders with dilated cardiomyopathy and variable skeletal muscle involvement are caused by mutations in LMNA, which encodes A-type nuclear lamins. How alterations in A-type lamins, intermediate filament proteins of the nuclear envelope expressed in most differentiated somatic cells, cause cardiomyopathy is only poorly understood. We previously demonstrated abnormal activation of the extracellular signal-regulated kinase (ERK) branch of the mitogen-activated protein kinase (MAPK) signaling cascade in hearts of Lmna H222P "knock in" mice, a model of autosomal Emery-Dreifuss muscular dystrophy. We therefore treated LmnaH222P/H222P mice that develop cardiomyopathy with PD98059, an inhibitor of ERK activation. Systemic treatment of LmnaH222P/H222P mice with PD98059 inhibited ERK phosphorylation and blocked activation of downstream genes in heart. It also blocked increased expression of RNAs encoding natriuretic peptide precursors and proteins involved in sarcomere organization that occurred in placebo treated mice. Histological analysis and echocardiography demonstrated that treatment with PD98059 delayed the development of left ventricular dilatation. PD98059-treated LmnaH222P/H222P mice had normal cardiac ejection fractions assessed by echocardiography when placebo-treated mice had a 30% decrease. These results emphasize the role of ERK activation in the development of cardiomyopathy caused by LMNA mutations. They further provide proof of principle for ERK inhibition as a therapeutic option to prevent or delay heart failure in humans with Emery-Dreifuss muscular dystrophy and related disorders caused by mutations in LMNA.
Present Address: Santhera Pharmaceuticals Ltd, Liestal, Switzerland.
Present Address: Department of Cardiology and Pneumology, Center of Molecular Cardiology, Georg-August University, Göttingen, Germany.