Published Online
on March 3, 2008

A more recent version of this article appeared on March 18, 2008

This Article Full Text (PDF) Data Supplement Correction (v117,pe314) All Versions of this Article: 117/11/1423    most recent CIRCULATIONAHA.107.728865v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Kontaridis, M. I. Articles by Neel, B. G. PubMed PubMed Citation Articles by Kontaridis, M. I. Articles by Neel, B. G. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Nucleotide Protein UniGene Medline Plus Health Information Cardiomyopathy Related Collections Biochemistry and metabolism Genetics of cardiovascular disease Animal models of human disease Cell signalling/signal transduction Genetically altered mice Growth factors/cytokines Physiological and pathological control of gene expression Related Article

Submitted on May 11, 2007
Accepted on January 2, 2008

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, and 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.

^* To whom correspondence should be addressed. E-mail: mkontari{at}bidmc.harvard.edu.

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.

Key words: cardiomyopathies • heart diseases • molecular biology • myocardium • myocytes • signal transduction

Related Article:

Clinical Summaries
Circulation 2008 117: 1353. [Full Text]