This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 104/7/905    most recent CIRCRESAHA.108.188292v1 Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, W. Articles by Wang, X. Search for Related Content PubMed PubMed Citation Articles by Liu, W. Articles by Wang, X. Related Collections Remodeling Cell signalling/signal transduction Genetically altered mice Hypertrophy

(Circulation Research. 2009;104:905.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Cardiac-Specific Deletion of Mkk4 Reveals Its Role in Pathological Hypertrophic Remodeling but Not in Physiological Cardiac Growth

Wei Liu^*, Min Zi^*, Jiawei Jin^*, Sukhpal Prehar, Delvac Oceandy, Tomomi E. Kimura, Ming Lei, Ludwig Neyses, Arthur H. Weston, Elizabeth J. Cartwright, Xin Wang

From the Faculty of Medical and Human Sciences (W.L., M.Z., S.P., D.O., M.L., L.N., E.J.C.) and Faculty of Life Sciences (J.J., T.E.K., A.H.W., X.W.), University of Manchester, United Kingdom.

Correspondence to Dr Xin Wang, Faculty of Life Sciences, the University of Manchester, CTF Building, Grafton St, Manchester M13 9NT, United Kingdom. E-mail xin.wang{at}manchester.ac.uk

Mitogen-activated protein kinase kinase (MKK)4 is a critical member of the mitogen-activated protein kinase family. It is able to activate the c-Jun NH₂-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase in response to environmental stresses. JNK and p38 are strongly implicated in pathological cardiac hypertrophy and heart failure; however, the regulatory mechanism whereby the upstream kinase MKK4 activates these signaling cascades in the heart is unknown. To elucidate the biological function of MKK4, we generated mice with a cardiac myocyte-specific deletion of mkk4 (MKK4^cko mice). In response to pressure overload or chronic β-adrenergic stimulation, upregulated NFAT (nuclear factor of activated T-cell) transcriptional activity associated with exacerbated cardiac hypertrophy and the appearance of apoptotic cardiomyocytes were observed in MKK4^cko mice. However, when subjected to swimming exercise, MKK4^cko mice displayed a similar level of physiological cardiac hypertrophy compared to controls (MKK4^f/f). In addition, we also discovered that MKK4 expression was significantly reduced in heart failure patients. In conclusion, this study demonstrates for the first time that MKK4 is a key mediator which prevents the transition from an adaptive response to maladaptive cardiac hypertrophy likely involving the regulation of the NFAT signaling pathway.

Key Words: cardiac hypertrophy • signal transduction • genetically modified mice

This article has been cited by other articles:

				D. Oceandy, A. Pickard, S. Prehar, M. Zi, T. M.A. Mohamed, P. J. Stanley, F. Baudoin-Stanley, R. Nadif, S. Tommasi, G. P. Pfeifer, et al. Tumor Suppressor Ras-Association Domain Family 1 Isoform A Is a Novel Regulator of Cardiac Hypertrophy Circulation, August 18, 2009; 120(7): 607 - 616. [Abstract] [Full Text] [PDF]