Cardiac-specific deletion of mkk4 reveals its role in pathological hypertrophic remodeling but not in physiological cardiac growth.
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.
Liu
Wei
W
Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom.
Zi
Min
M
Jin
Jiawei
J
Prehar
Sukhpal
S
Oceandy
Delvac
D
Kimura
Tomomi E
TE
Lei
Ming
M
Neyses
Ludwig
L
Weston
Arthur H
AH
Cartwright
Elizabeth J
EJ
Wang
Xin
X
D000222:Adaptation, Physiological; D000818:Animals; D017209:Apoptosis; D001794:Blood Pressure; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D006321:Heart / Q000254:growth & development* / Q000503:physiopathology; D006333:Heart Failure / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D007545:Isoproterenol; D048670:MAP Kinase Kinase 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D013550:Swimming; D013997:Time Factors; D014158:Transcription, Genetic
D050778:NFATC Transcription Factors; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; C482562:Map2k4 protein, mouse; D007545:Isoproterenol