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

Research output: Contribution to journalArticlepeer-review


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 (MKK4f/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. © 2009 American Heart Association, Inc.
Original languageEnglish
Pages (from-to)905-914
Number of pages9
JournalCirculation research
Issue number7
Publication statusPublished - 10 Apr 2009


  • Cardiac hypertrophy
  • Genetically modified mice
  • Signal transduction


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