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(Circulation. 2008;117:1423-1435.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Deletion of Ptpn11 (Shp2) in Cardiomyocytes Causes Dilated Cardiomyopathy via Effects on the Extracellular Signal–Regulated Kinase/Mitogen-Activated Protein Kinase and RhoA Signaling Pathways

Maria I. Kontaridis, PhD; Wentian Yang, MD, PhD; Kendra K. Bence, PhD; Darragh Cullen, MA; Bo Wang, MD; Natalya Bodyak, PhD; Qingen Ke, MD; Aleksander Hinek, MD, PhD, DSc; Peter M. Kang, MD; Ronglih Liao, PhD; Benjamin G. Neel, MD, PhD

From the Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass (M.I.K., W.Y., K.K.B., B.G.N.); Cardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (D.C., B.W., R.L.); Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Mass (N.B., Q.K., P.M.K.); and Cardiovascular Research Program, Hospital for Sick Children and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (A.H). Dr Yang currently is at the Department of Orthopedics, Brown University Alpert Medical School, Providence, RI. Dr Bence currently is at the Department of Animal Biology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia. Dr Neel currently is at the Ontario Cancer Institute, Toronto, Ontario, Canada.

Correspondence to Dr Maria Irene Kontaridis, Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, NRB, Room 1036, 77 Ave Louis Pasteur, Boston, MA 02115. E-mail mkontari{at}bidmc.harvard.edu

Received May 11, 2007; accepted January 2, 2008.

Background— Heart failure is the leading cause of death in the United States. By delineating the pathways that regulate cardiomyocyte function, we can better understand the pathogenesis of cardiac disease. Many cardiomyocyte signaling pathways activate protein tyrosine kinases. However, the role of specific protein tyrosine phosphatases (PTPs) in these pathways is unknown.

Methods and Results— Here, we show that mice with muscle-specific deletion of Ptpn11, the gene encoding the SH2 domain–containing PTP Shp2, rapidly develop a compensated dilated cardiomyopathy without an intervening hypertrophic phase, with signs of cardiac dysfunction appearing by the second postnatal month. Shp2-deficient primary cardiomyocytes are defective in extracellular signal–regulated kinase/mitogen-activated protein kinase (Erk/MAPK) activation in response to a variety of soluble agonists and pressure overload but show hyperactivation of the RhoA signaling pathway. Treatment of primary cardiomyocytes with Erk1/2- and RhoA pathway–specific inhibitors suggests that both abnormal Erk/MAPK and RhoA activities contribute to the dilated phenotype of Shp2-deficient hearts.

Conclusions— Our results identify Shp2 as the first PTP with a critical role in adult cardiac function, indicate that in the absence of Shp2 cardiac hypertrophy does not occur in response to pressure overload, and demonstrate that the cardioprotective role of Shp2 is mediated via control of both the Erk/MAPK and RhoA signaling pathways.

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