MEF2 transcriptional activity maintains mitochondrial adaptation in cardiac pressure overload

被引：21
作者：
el Azzouzi, Hamid [1 ,2 ,3 ]
van Oort, Ralph J. [2 ,3 ]
van der Nagel, Roel [2 ,3 ]
Sluiter, Wim [4 ]
Bergmann, Martin W. [5 ]
De Windt, Leon J. [1 ,2 ,3 ]
机构：
[1] Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Cardiol, Fac Hlth Med & Life Sci, Maastricht, Netherlands
[2] Royal Netherlands Acad Sci, Hubrecht Inst, Utrecht, Netherlands
[3] Royal Netherlands Acad Sci, Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands
[4] Erasmus MC, Dept Neurol, Rotterdam, Netherlands
[5] Charite, Dept Cardiol, Franz Volhard Klin, Max Delbruck Ctr Mol Med, D-13353 Berlin, Germany
来源：
EUROPEAN JOURNAL OF HEART FAILURE | 2010年 / 12卷 / 01期
关键词：
MEF2; NADH dehydrogenase subunit 6; Transverse aortic constriction; Mitochondria; Heart failure; Reactive oxygen species; HEREDITARY-OPTIC-NEUROPATHY; ENHANCER FACTOR-2 MEF2; INDUCED HEART-FAILURE; COMPLEX-I; OXIDATIVE STRESS; INDUCED APOPTOSIS; GENE-EXPRESSION; TRANSGENIC MICE; DOWN-REGULATION; HYPERTROPHY;
D O I：
10.1093/eurjhf/hfp165
中图分类号：
R5 [内科学];
学科分类号：
1002 ; 100201 ;
摘要：
The transcription factor MEF2 is a downstream target for several hypertrophic signalling pathways in the heart, suggesting that MEF2 may act as a valuable therapeutic target in the treatment of heart failure. In this study, we investigated the potential benefits of overall MEF2 inhibition in a mouse model of chronic pressure overloading, by subjecting transgenic mice expressing a dominant negative form of MEF2 (DN-MEF2 Tg) in the heart, to transverse aortic constriction (TAC). Histological analysis revealed no major differences in cardiac remodelling between DN-MEF2 Tg and control mice after TAC. Surprisingly, echocardiographic analysis revealed that DN-MEF2 Tg mice had a decrease in cardiac function compared with control animals. Analysis of the mitochondrial respiratory chain showed that DN-MEF2 Tg mice displayed lower expression of NADH dehydrogenase subunit 6 (ND6), part of mitochondrial Complex I. The reduced expression of ND6 in DN-MEF2 Tg mice after pressure overload correlated with an increase in cell death secondary to overproduction of reactive oxygen species (ROS). Our data suggest that MEF2 transcriptional activity is required for mitochondrial function and its inhibition predisposes the heart to impaired mitochondrial function, overproduction of ROS, enhanced cell death, and cardiac dysfunction, following pressure overload.
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页码：4 / 12
页数：9
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