Reference : Cardiac-specific deletion of mkk4 reveals its role in pathological hypertrophic remod...
Scientific journals : Article
Human health sciences : Cardiovascular & respiratory systems
Cardiac-specific deletion of mkk4 reveals its role in pathological hypertrophic remodeling but not in physiological cardiac growth.
Liu, Wei [> >]
Zi, Min [> >]
Jin, Jiawei [> >]
Prehar, Sukhpal [> >]
Oceandy, Delvac [> >]
Kimura, Tomomi E. [> >]
Lei, Ming [> >]
Neyses, Ludwig mailto [University of Luxembourg > Research Office]
Weston, Arthur H. [> >]
Cartwright, Elizabeth J. [> >]
Wang, Xin [> >]
Circulation Research
Yes (verified by ORBilu)
United States
[en] Adaptation, Physiological ; Animals ; Apoptosis ; Blood Pressure ; Cardiomegaly/chemically induced/enzymology/pathology/physiopathology ; Disease Models, Animal ; Heart/growth & development/physiopathology ; Heart Failure/enzymology/pathology/physiopathology ; Isoproterenol ; MAP Kinase Kinase 4/deficiency/genetics/metabolism ; Male ; Mice ; Mice, Knockout ; Myocardium/enzymology/pathology ; NFATC Transcription Factors/metabolism ; Signal Transduction ; Swimming ; Time Factors ; Transcription, Genetic
[en] 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 NH(2)-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 beta-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.

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