NADPH Oxidase 4 Regulates Cardiomyocyte Differentiation via Redox Activation of c-Jun Protein and the cis-Regulation of GATA-4 Gene Transcription

Murray, Thomas; Smyrnias, Ioannis; Shah, Ajay M.; Brewer, Alison C.

doi:10.1074/jbc.m112.439844

Cited by 47 publications

(38 citation statements)

References 61 publications

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“…However, in the current study, we used an ex vivo cell culture model and determined that knocking down Nox4 in cells from p47 phoxϪ/Ϫ mice blocked temporal osteoblastic cell differentiation signaling. These data are consistent with recent findings demonstrating that Nox4 is required for cardiomyocyte and adipocyte differentiation in vitro via redox activation (31), and ROS-dependent signaling pathways are also known to play an important role in osteoblast differentiation (32). Our data therefore suggest that Nox2 and Nox4 function differently during early development and skeletal involution to preserve different roles on osteoblast differentiation and proliferation, respectively.…”

Section: Discussionsupporting

confidence: 93%

p47 -Nox2-dependent ROS Signaling Inhibits Early Bone Development in Mice but Protects against Skeletal Aging

Chen

Lazarenko

Blackburn

et al. 2015

Journal of Biological Chemistry

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Background: How reduced ROS signaling regulates inflammation and remodeling in bone remains unknown. Results: Age-related switch of bone mass in p47 phox -deficient mice occurs through an increased inflammatory milieu in bone. Conclusion: p47phox -Nox2-dependent physiological ROS signaling suppresses inflammation in aging. Significance: p47phox -Nox2 and Nox4 may play different roles during early development and skeletal involution because they serve unique functions on osteoblast differentiation and proliferation.

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Section: Discussionsupporting

confidence: 93%

p47 -Nox2-dependent ROS Signaling Inhibits Early Bone Development in Mice but Protects against Skeletal Aging

Chen

Lazarenko

Blackburn

et al. 2015

Journal of Biological Chemistry

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“…Both Nox2 and Nox4 exhibited increased expression over the course of c-kit ϩ cell differentiation, with Nox4 showing upregulation somewhat earlier than Nox2. This is consistent with evidence that both of these homologs are expressed in multiple developing and mature cardiac cell types (4,8,9,16,26,31,59). Previously, we reported that c-kit ϩ cells differentiate into all three lineages of the heart in vitro (52), so to determine whether Nox2 and/or Nox4 are functionally linked to c-kit ϩ CPC differentiation into smooth muscle, cardiac muscle, and/or endothelial cells, we went on to utilize genesilencing viruses targeted selectively to each of these two homologs (19,20,37).…”

Section: Discussionsupporting

confidence: 91%

“…To determine whether Nox2 and Nox4 are functionally linked to c-kit ϩ precursor cell status and/or cardiac cell differentiation in vitro, we utilized adenoviruses encoding U6 promoter-driven siRNAs targeted to Nox2 (AdsiNox2) or Nox4 (AdsiNox4). These siRNAs were previously established and fully characterized in our laboratory (19,20,37) and have been used successfully by other researchers in multiple cell types and experimental settings (27,31). Importantly, we have demonstrated that these viruses efficiently and selectively silence Nox2 and Nox4 at the mRNA and protein levels and significantly reduce ROS formation in cultured cardiomyocytes and in vivo (19,20,37).…”

Section: C-kit ϩ Cpcs Exhibit Reduced Overall Ros Levels In Vitro Andmentioning

confidence: 84%

Nox2 and Nox4 influence neonatal c-kit⁺ cardiac precursor cell status and differentiation

Nadworny

Guruju

Poor

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Redox status has emerged as critical in modulating stemness and lineage commitment in several precursor cell types. However, a role for redox genes, specifically NADPH oxidases (Nox), in cardiac precursor cells (CPCs) has not been established. We tested whether CPCs marked by type III receptor tyrosine kinase c-kit (c-kit(+)) exhibit a unique NADPH oxidase signature that confers precursor status and whether alterations in this profile are functionally linked to changes in lineage specification. Dihydroethidium (DHE) microfluorography indicated reduced basal reactive oxygen species (ROS) formation within early postnatal c-kit(+) CPCs. Real-time quantitative PCR revealed downregulation of ROS generator Nox2 and its subunit p67(phox) in c-kit(+) CPCs under basal conditions but upregulation of Nox2 and Nox4 over the course of differentiation. Adenoviral silencing of Nox2 and Nox4 increased expression of CPC markers c-kit and Flk-1 and blunted smooth and cardiac muscle differentiation, respectively, while overexpression of Nox2 and Nox4 significantly reduced c-kit expression. These changes were accompanied by altered expression of transcription factors regulating cardiac lineage commitment, Gata6 and Gata4, and cytokine transforming growth factor (TGF)-β1. Similar to other precursor cell types, RT(2)Profiler PCR Arrays revealed that c-kit(+) CPCs also exhibit enhanced antioxidant capacity at the mRNA level. In conclusion, we report that c-kit(+) CPCs demonstrate reduced Nox2 expression and ROS levels and that increases in Nox2 and Nox4 influence their differentiation into mature cells. We speculate that ROS generators Nox2 and Nox4, along with the antioxidant genes identified by PCR Arrays, may be novel targets in CPCs that could prove useful in cell-based therapy of the heart.

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“…It is therefore tempting to speculate that upregulation of JUN, NR2F2, and NR4A2 is a compensatory response of MA-10 cells to offset the decrease in steroidogenic gene expression or to increase Gata4 expression itself in MA-10 cells deficient in GATA4. The demonstration that JUN can directly activate Gata4 transcription would support at least the latter possibility (Murray et al 2013). …”

Section: Discussionmentioning

confidence: 95%

GATA4 knockdown in MA-10 Leydig cells identifies multiple target genes in the steroidogenic pathway

Bergeron¹,

Nadeau²,

Viger³

2015

Reproduction

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GATA4 is an essential transcription factor required for the initiation of genital ridge formation, for normal testicular and ovarian differentiation at the time of sex determination, and for male and female fertility in adulthood. In spite of its crucial roles, the genes and/or gene networks that are ultimately regulated by GATA4 in gonadal tissues remain to be fully understood. This is particularly true for the steroidogenic lineages such as Leydig cells of the testis where many in vitro (promoter) studies have provided good circumstantial evidence that GATA4 is a key regulator of Leydig cell gene expression and steroidogenesis, but formal proof is still lacking. We therefore performed a microarray screening analysis of MA-10 Leydig cells in which Gata4 expression was knocked down using an siRNA strategy. Analysis identified several GATA4-regulated pathways including cholesterol synthesis, cholesterol transport, and especially steroidogenesis. A decrease in GATA4 protein was associated with decreased expression of steroidogenic genes previously suspected to be GATA4 targets such as Cyp11a1 and Star. Gata4 knockdown also led to an important decrease in other novel steroidogenic targets including Srd5a1, Gsta3, Hsd3b1, and Hsd3b6, as well as genes known to participate in cholesterol metabolism such as Scarb1, Ldlr, Soat1, Scap, and Cyp51. Consistent with the decreased expression of these genes, a reduction in GATA4 protein compromised the ability of MA-10 cells to produce steroids both basally and under hormone stimulation. These data therefore provide strong evidence that GATA4 is an essential transcription factor that sits atop of the Leydig cell steroidogenic program.

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NADPH Oxidase 4 Regulates Cardiomyocyte Differentiation via Redox Activation of c-Jun Protein and the cis-Regulation of GATA-4 Gene Transcription

Cited by 47 publications

References 61 publications

p47 -Nox2-dependent ROS Signaling Inhibits Early Bone Development in Mice but Protects against Skeletal Aging

p47 -Nox2-dependent ROS Signaling Inhibits Early Bone Development in Mice but Protects against Skeletal Aging

Nox2 and Nox4 influence neonatal c-kit⁺ cardiac precursor cell status and differentiation

GATA4 knockdown in MA-10 Leydig cells identifies multiple target genes in the steroidogenic pathway

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NADPH Oxidase 4 Regulates Cardiomyocyte Differentiation via Redox Activation of c-Jun Protein and the cis-Regulation of GATA-4 Gene Transcription

Cited by 47 publications

References 61 publications

p47 -Nox2-dependent ROS Signaling Inhibits Early Bone Development in Mice but Protects against Skeletal Aging

p47 -Nox2-dependent ROS Signaling Inhibits Early Bone Development in Mice but Protects against Skeletal Aging

Nox2 and Nox4 influence neonatal c-kit+ cardiac precursor cell status and differentiation

GATA4 knockdown in MA-10 Leydig cells identifies multiple target genes in the steroidogenic pathway

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Nox2 and Nox4 influence neonatal c-kit⁺ cardiac precursor cell status and differentiation