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 Resjournal_title
Circulation researchauthors
Liu W,Zi M,Jin J,Prehar S,Oceandy D,Kimura TE,Lei M,Neyses L,Weston AH,Cartwright EJ,Wang Xdoi
10.1161/CIRCRESAHA.108.188292subject
Has Abstractpub_date
2009-04-10 00:00:00pages
905-14issue
7eissn
0009-7330issn
1524-4571pii
CIRCRESAHA.108.188292journal_volume
104pub_type
杂志文章abstract:RATIONALE:Pulmonary arterial hypertension (PAH) remains a progressive and eventually lethal disease characterized by increased pulmonary vascular resistance because of loss of functional lung microvasculature, primarily at the distal (intracinar) arteriolar level. Cell-based therapies offer the potential to repair and ...
journal_title:Circulation research
pub_type: 杂志文章,多中心研究
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更新日期:2008-06-20 00:00:00
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pub_type: 杂志文章
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更新日期:2012-01-20 00:00:00
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更新日期:1998-09-21 00:00:00
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更新日期:2017-01-06 00:00:00
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更新日期:1983-08-01 00:00:00
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更新日期:1981-03-01 00:00:00
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更新日期:2008-08-15 00:00:00
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更新日期:1984-11-01 00:00:00
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pub_type: 杂志文章,多中心研究,随机对照试验
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更新日期:2015-01-02 00:00:00
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pub_type: 杂志文章
doi:
更新日期:2000-06-23 00:00:00
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pub_type: 杂志文章,评审
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更新日期:2007-02-16 00:00:00