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

Abstract:

: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.

journal_name

Circ Res

journal_title

Circulation research

authors

Liu W,Zi M,Jin J,Prehar S,Oceandy D,Kimura TE,Lei M,Neyses L,Weston AH,Cartwright EJ,Wang X

doi

10.1161/CIRCRESAHA.108.188292

subject

Has Abstract

pub_date

2009-04-10 00:00:00

pages

905-14

issue

7

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.108.188292

journal_volume

104

pub_type

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