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Cardiac-specific deletion of mkk4 reveals its role in pathological hypertrophic remodeling but not in physiological cardiac growth.

Circulation Research
Ovid Technologies Wolters Kluwer -American Heart Association
Publication Date
  • Adaptation
  • Physiological
  • Animals
  • Apoptosis
  • Blood Pressure
  • Chemically Induced: Cardiomegaly
  • Disease Models
  • Animal
  • Growth & Development: Heart
  • Enzymology: Heart Failure
  • Isoproterenol
  • Deficiency: Map Kinase Kinase 4
  • Male
  • Mice
  • Mice
  • Knockout
  • Enzymology: Myocardium
  • Metabolism: Nfatc Transcription Factors
  • Signal Transduction
  • Swimming
  • Time Factors
  • Transcription
  • Genetic
  • Biology
  • Ecology
  • Geography
  • Medicine


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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