Differential Regulation of the Cardiac Sodium Calcium Exchanger Promoter in Adult and Neonatal Cardiomyocytes by Nkx2.5 and Serum Response Factor

Müller, Joachim G.; Thompson, Jerry T.; Edmonson, Angela M.; Rackley, Mary S.; Kasahara, Hideko; Izumo, Seigo; McQuinn, Tim; Menick, Donald R.; O’Brien, Terrence X.

doi:10.1006/jmcc.2002.2019

Cited by 23 publications

(14 citation statements)

References 40 publications

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“…[117][118][119][120][121][122] In addition, direct downstream targets for Csx/ Nkx2-5 (such as ANP, 52,123 cardiac ␣-actin, 124 A 1 adenosine receptor, 125 calreticulin, 126 connexin40, 127 and NCX1) have been identified. 128 These results indicate a functional role of Csx/Nkx2-5 in the transcriptional regulation of a cardiac gene program. In contrast to the essential role of Csx/Nkx2-5 during embryogenesis, its functional role in the postnatal heart has not been fully determined.…”

Section: Cardiac Homeobox Transcriptionmentioning

confidence: 78%

Roles of Cardiac Transcription Factors in Cardiac Hypertrophy

Akazawa

Komuro

2003

Circulation Research

371

282

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Key Words: cardiac transcription factors Ⅲ gene expression Ⅲ cardiac hypertrophy Ⅲ cardiogenesis C ardiomyocytes are terminally differentiated and lose their ability to proliferate soon after birth. Thereafter, cardiomyocytes grow in cell size without cell division to adapt to a demand for an increased workload. In a number of pathological conditions (eg, hypertension, valvular disease, myocardial infarction, and cardiomyopathy) that impose overwork on the heart, postnatal cardiomyocytes undergo cardiac hypertrophy. Although cardiac hypertrophy is initially compensatory for an increased workload, prolongation of this process leads to congestive heart failure, arrhythmia, and sudden death. 1,2 At the cellular level, cardiac hypertrophy is characterized by an increase in cell size and protein synthesis and reactivation of the fetal gene program. [3][4][5] In addition, recent large-scale expression analyses have identified numerous genes other than fetal genes or immediateearly genes that were upregulated in hypertrophied hearts, including genes encoding proteins involved in signaling pathways and energy metabolism. 6,7 The points at issue are how extracellular hypertrophic stimulation is perceived and converted into intracellular signals and how these signals change the transcriptional program that eventually leads to cardiac hypertrophy. With regard to the differential gene expression induced by hypertrophic stimulation, it is reasonable to assume that cardiac transcription factors play the leading part, because they directly regulate a number of cardiac genes that are upregulated in hypertrophied myocardium.Cardiac transcription factors are defined, in this context, as essential transcriptional activators that are expressed predominantly in the myocardium and that regulate the expression of the Original

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Section: Cardiac Homeobox Transcriptionmentioning

confidence: 78%

Roles of Cardiac Transcription Factors in Cardiac Hypertrophy

Akazawa

Komuro

2003

Circulation Research

371

282

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“…Some of these SRF targets may be less dependent on SRF activation at this early stage. Accordingly, interactions between Nkx2.5 and SRF in heart-specific gene regulation were shown to produce different transcriptional responses in cardiomyocytes from adults versus those from neonates (33). Second, some mRNAs might be synthesized before inactivation of the Srf gene and be more stable.…”

Section: Discussionmentioning

confidence: 99%

Targeted Inactivation of Serum Response Factor in the Developing Heart Results in Myocardial Defects and Embryonic Lethality

Parlakian

Tuil²,

Hamard

et al. 2004

Molecular and Cellular Biology

188

179

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Serum response factor (SRF) is at the confluence of multiple signaling pathways controlling the transcription of immediate-early response genes and muscle-specific genes. There are active SRF target sequences in more than 50 genes expressed in the three muscle lineages including normal and diseased hearts. However, the role of SRF in heart formation has not been addressed in vivo thus far due to the early requirement of SRF for mesoderm formation. We have generated a conditional mutant of SRF by using Cre-LoxP strategy that will be extremely useful to study the role of SRF in embryonic and postnatal cardiac functions, as well as in other tissues. This report shows that heart-specific deletion of SRF in the embryo by using a new ␤MHC-Cre transgenic mouse line results in lethal cardiac defects between embryonic day 10.5 (E10.5) and E13.5, as evidenced by abnormally thin myocardium, dilated cardiac chambers, poor trabeculation, and a disorganized interventricular septum. At E9.5, we found a marked reduction in the expression of essential regulators of heart development, including Nkx2.5, GATA4, myocardin, and the SRF target gene c-fos prior to overt maldevelopment. We conclude that SRF is crucial for cardiac differentiation and maturation, acting as a global regulator of multiple developmental genes.

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“…Recombinant adenovirus encoding human Nkx2.5, tagged at its aminoterminus with a short hemagglutinin (HA) peptide sequence, was prepared as described previously (Müller et al, 2002). Control virus, encoding h-galactosidase, was kindly provided by Dr. L. de Windt (Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht, The Netherlands).…”

Section: Recombinant Adenoviral Infectionmentioning

confidence: 99%