Morphogenesis of the right ventricle requires myocardial expression of Gata4

Zeisberg, Elisabeth M.; Ma, Qing; Juraszek, Amy L.; Moses, Kelvin A.; Schwartz, Robert J.; Izumo, Seigo; Pu, William T.

doi:10.1172/jci23769

Cited by 239 publications

(216 citation statements)

References 59 publications

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“…By dividing the relative difference in HW͞BW (G4D͞WT ϭ 0.85) by the relative difference in cardiomyocyte size (G4D͞WT ϭ 1.22), we calculated that the cardiomyocyte number in G4D mice was 70% of wild-type, i.e., a 30% reduction. We previously showed that the level of Gata4 expression is an important regulator of cardiomyocyte proliferation in the prenatal heart (10). Therefore, we suspected that the decrease in cell number reflected a prenatal decrease in cardiomyocyte proliferation.…”

Section: Resultsmentioning

confidence: 95%

“…Traditional loss-of-function approaches have been complicated by early embryonic lethality in Gata4 null embryos (8,9). In our hands, embryos with embryonic cardiac-restricted Gata4 inactivation also suffered from fetal demise (10). These embryos died from heart failure, and the mutant hearts were characterized by marked myocardial hypoplasia due to decreased cardiomyocyte proliferation (10).…”

mentioning

confidence: 82%

“…By direct measurement, we determined that cardiomyocyte number was reduced to a similar degree (24% reduction) in fetal G4D hearts. Reduced Gata4 dosage in fetal cardiomyocytes resulted in decreased cardiomyocyte proliferation (10,11). Gata4 also promotes cardiomyocyte differentiation from progenitor cells (23).…”

Section: Gata4 Regulation Of Cardiomyocyte Hypertrophy Based On In Vmentioning

confidence: 99%

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Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure

Bisping

Ikeda

Kong

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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168

147

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An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy. In cultured cardiomyocytes, the transcription factor Gata4 is required for agonist-induced hypertrophy. We hypothesized that, in the intact organism, Gata4 is an important regulator of postnatal heart function and of the hypertrophic response of the heart to pathological stress. To test this hypothesis, we studied mice heterozygous for deletion of the second exon of Gata4 (G4D). At baseline, G4D mice had mild systolic and diastolic dysfunction associated with reduced heart weight and decreased cardiomyocyte number. After transverse aortic constriction (TAC), G4D mice developed overt heart failure and eccentric cardiac hypertrophy, associated with significantly increased fibrosis and cardiomyocyte apoptosis. Inhibition of apoptosis by overexpression of the insulin-like growth factor 1 receptor prevented TAC-induced heart failure in G4D mice. Unlike WT-TAC controls, G4D-TAC cardiomyocytes hypertrophied by increasing in length more than width. Gene expression profiling revealed up-regulation of genes associated with apoptosis and fibrosis, including members of the TGF-␤ pathway. Our data demonstrate that Gata4 is essential for cardiac function in the postnatal heart. After pressure overload, Gata4 regulates the pattern of cardiomyocyte hypertrophy and protects the heart from load-induced failure.apoptosis ͉ hypertrophy ͉ fibrosis ͉ gene expression ͉ Igf-1 H eart failure is one of the leading causes of morbidity and mortality in industrialized countries (1). An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy (2). This is characterized by increased cardiomyocyte size, increased protein synthesis, and altered gene expression. Over time, the changes in gene expression can be maladaptive and contribute to progression of heart failure (3).A large body of evidence suggests that the transcription factor Gata4 is an important regulator of cardiomyocyte hypertrophy (4, 5). Gata4 has been implicated in the regulation of an array of cardiac genes in response to hypertrophic agonists, including atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), skeletal ␣-actin, ␣-myosin heavy chain (␣-MHC), and ␤-myosin heavy chain (␤-MHC) (4, 5). Gata4 overexpression is sufficient to induce the hypertrophic response in cultured neonatal cardiomyocytes and transgenic mice (6). Moreover, the hypertrophic response of cultured neonatal rat cardiomyocytes requires Gata4 (6, 7).We sought to investigate the in vivo role of Gata4 in regulating postnatal heart function and the response to hypertrophic stress. Traditional loss-of-function approaches have been complicated by early embryonic lethality in Gata4 null embryos (8, 9). In our hands, embryos with embryonic cardiac-restricted Gata4 inactivation also suffered from fetal demise (10). These embryos died from heart failure, and the mutant hearts were characterized by marked myocardial hypoplasia due to decreased ca...

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Section: Resultsmentioning

confidence: 95%

mentioning

confidence: 82%

Section: Gata4 Regulation Of Cardiomyocyte Hypertrophy Based On In Vmentioning

confidence: 99%

See 1 more Smart Citation

Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure

Bisping

Ikeda

Kong

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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168

147

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“…The phenotype of zebrafish gata5 mutants closely resembles the cardiac phenotypes in gata4 mutant mice. Myocardium-restricted deletion of murine gata4 or gata4/gata6 double heterozygote causes a marked reduction in cardiomyocyte proliferation and results in hypoplastic hearts (5)(6)(7). Although it seems to be clear that certain levels of GATA activity are required to drive myocardial proliferative growth, opposing signals might also be necessary to constrain the excessive cardiac growth during development.…”

mentioning

confidence: 99%

Vertebrate heart growth is regulated by functional antagonism between Gridlock and Gata5

Jia

King²,

Chopra³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Embryonic organs attain their final dimensions through the generation of proper cell number and size, but the control mechanisms remain obscure. Here, we establish Gridlock (Grl), a Hairy-related basic helix-loop-helix (bHLH) transcription factor, as a negative regulator of cardiomyocyte proliferative growth in zebrafish embryos. Mutations in grl cause an increase in expression of a group of immediate-early growth genes, myocardial genes, and development of hyperplastic hearts. Conversely, cardiomyocytes with augmented Grl activity have diminished cell volume and fail to divide, resulting in a marked reduction in heart size. Both bHLH domain and carboxyl region are required for Grl negative control of myocardial proliferative growth. These Grl-induced cardiac effects are counterbalanced by the transcriptional activator Gata5 but not Gata4, which promotes cardiomyocyte expansion in the embryo. Biochemical analyses show that Grl forms a complex with Gata5 through the carboxyl region and can repress Gata5-mediated transcription via the bHLH domain. Hence, our studies suggest that Grl regulates embryonic heart growth via opposing Gata5, at least in part through their protein interactions in modulating gene expression.cardiomyocyte ͉ proliferation ͉ size control ͉ transcription T he embryonic heart grows through a combination of cardiomyocyte proliferation and an increase in cell mass due to the generation of myofibrillar arrays (1). Cardiac proliferation diminishes progressively after birth, and postmitotic hypertrophy in the adult heart provides most of the adaptive responses necessary to supply increased cardiac output (2). Despite recent progress that has been made in the regulation of postnatal cardiac hypertrophy, the mechanisms and pathways that control embryonic heart growth are poorly delineated. It is not known what molecular signals restrain cardiomyocyte proliferative growth in the embryonic heart. The GATA zinc-finger transcription factors promote myocardial differentiation and expansion. Among the three gata genes (gata4, gata5, and gata6) in zebrafish, gata5 plays the most prominent role in heart growth and development (3). Mutations in gata5 in zebrafish cause a reduction in expression of early and late myocardial genes and a decrease in cardiac progenitor cells and proliferative cardiomyocytes, resulting in small hearts. Forced gata5 expression in the zebrafish embryo increases heart size and occasionally produces ectopically beating myocardial tissue (4). The phenotype of zebrafish gata5 mutants closely resembles the cardiac phenotypes in gata4 mutant mice. Myocardium-restricted deletion of murine gata4 or gata4/gata6 double heterozygote causes a marked reduction in cardiomyocyte proliferation and results in hypoplastic hearts (5-7). Although it seems to be clear that certain levels of GATA activity are required to drive myocardial proliferative growth, opposing signals might also be necessary to constrain the excessive cardiac growth during development.grl encodes a hairy-related basic helix-loop-h...

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“…Both conditional knockout mice lacking GATA-4 in specific cardiomyocytes, as well as transgenic mice expressing only 30% of the normal levels of GATA-4 in the heart, display atrioventricular canal defects and a hypoplastic ventricular myocardium. Ventricular hypoplasia is thought to be associated with defects in cardiac morphogenesis and cardiomyocyte proliferation (10,11). However, the genetic programs under GATA-4 control are not well understood.…”

Section: Introductionmentioning

confidence: 99%

GATA-4 promotes the differentiation of P19 cells into cardiac myocytes

Chen²,

Liu³

et al. 2010

Int J Mol Med

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Abstract. The aim of this study was to investigate the effects of GATA-4 on the differentiation of P19 cells into cardiomyocytes and to examine the relationship between GATA-4 and cardiomyocytes. We constructed vectors to overexpress and silence GATA-4. These vectors, as well as empty ones were transfected into P19 cells. Subsequently, reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis were performed. The morphology of P19 cells during differentiation was observed using an inverted microscope. Total RNA was extracted from P19 cells. We used real-time PCR to evaluate the expression levels of 6 genes: GATA-4, GATA-6, transthyretin (TTR), ·-fetoprotein (AFP), Nkx2.5, and ·-myosin heavy chain (·-MHC). The gene expression pattern of these 6 genes is graphically shown for each group. The GATA-4 mRNA level in cells overexpressing GATA-4 was notably higher than that in the controls, whereas the levels in the controls were notably higher than those in the GATA-4-silenced P19 cells. The cell lines overexpressing GATA-4 expressed higher levels of Nkx2.5 and ·-MHC than the controls. However, the controls expressed higher levels of AFP, GATA-6 and TTR than the cells overexpressing GATA-4. The RNAi group expressed lower levels of TTR, Nkx2.5, and ·-MHC than the controls, but there were no differences in the RNAi group and the controls with regard to the expression levels of AFP and GATA-6. The gene expression pattern in the cells overexpressing GATA-4 was biased toward the Nkx2.5 and ·-MHC. On the other hand, the gene expression pattern in GATA-4-silenced cells and the controls was biased toward the TTR and AFP. The overexpression of GATA-4 enhances the differentiation of P19 cells into cardiac myocytes, whereas its down-regulation suppresses this trend.

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Morphogenesis of the right ventricle requires myocardial expression of Gata4

Cited by 239 publications

References 59 publications

Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure

Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure

Vertebrate heart growth is regulated by functional antagonism between Gridlock and Gata5

GATA-4 promotes the differentiation of P19 cells into cardiac myocytes

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