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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In response to numerous pathologic stimuli, the myocardium undergoes a hypertrophic response characterized by increased myocardial cell size and activation of fetal cardiac genes. We show that cardiac hypertrophy is induced by the calcium-dependent phosphatase calcineurin, which dephosphorylates the transcription factor NF-AT3, enabling it to translocate to the nucleus. NF-AT3 interacts with the cardiac zinc finger transcription factor GATA4, resulting in synergistic activation of cardiac transcription. Transgenic mice that express activated forms of calcineurin or NF-AT3 in the heart develop cardiac hypertrophy and heart failure that mimic human heart disease. Pharmacologic inhibition of calcineurin activity blocks hypertrophy in vivo and in vitro. These results define a novel hypertrophic signaling pathway and suggest pharmacologic approaches to prevent cardiac hypertrophy and heart failure.
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PMID:A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. 956 14

Previous studies have shown that patients with deletion of distal human chromosome arm 8p may have congenital heart disease and other physical anomalies. The gene encoding GATA-4, a zinc finger transcription factor implicated in cardiac gene expression and development, localizes to chromosome region 8p23.1. To examine whether GATA-4 deficiency is present in patients with monosomy of 8p23.1 with congenital heart disease, we performed fluorescence in situ hybridization (FISH) with a GATA4 probe on cells from a series of patients with interstitial deletion of 8p23.1. Four individuals with del(8)(p23.1) and congenital heart disease were found to be haploinsufficient at the GATA4 locus by FISH. The GATA4 gene was not deleted in a fifth patient with del(8)(p23.1) who lacked cardiac anomalies. FISH analysis on cells from 48 individuals with congenital heart disease and normal karyotypes failed to detect any submicroscopic deletions at the GATA4 locus. We conclude that haploinsufficiency at the GATA4 locus is often seen in patients with del(8)(p23.1) and congenital heart disease. Based on these findings and recent studies showing that haploinsufficiency for other cardiac transcription factor genes (e.g., TBX5, NKX2-5) causes congenital heart disease, we postulate that GATA-4 deficiency may contribute to the phenotype of patients with monosomy of 8p23.1.
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PMID:GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease. 1009 97

ZIC3 is a C2H2 zinc finger transcription factor that is involved in early patterning of the vertebrate embryo. Human patients with mutations in the X-linked ZIC3 gene have a complex developmental phenotype that includes laterality defects, congenital heart disease, and lumbosacral and anal anomalies, including neural tube defects. Similar phenotypes are found in the bent tail (BN) mouse, a spontaneous mutation that is associated with a submicroscopic deletion of the ZIC3 locus, as well as in a ZIC3 null allele generated through homologous recombination. These findings suggest that ZIC3 plays important roles during development in establishing a proper left-right axis and in midline neural patterning. This review will summarize our current understanding of the role of ZIC3 in patterning of the vertebrate embryo, based on studies in model organisms such as Xenopus and the mouse. In addition, a comparison of ZIC3 with other vertebrate ZIC family members will be provided.
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PMID:The role of ZIC3 in vertebrate development. 1290 May 69

Mutations in the zinc finger transcription factor ZIC3 cause X-linked heterotaxy and have also been identified in patients with isolated congenital heart disease (CHD). To determine the relative contribution of ZIC3 mutations to both heterotaxy and isolated CHD, we screened the coding region of ZIC3 in 194 unrelated patients, including 61 patients with classic heterotaxy, 93 patients with heart defects characteristic of heterotaxy, and 11 patients with situs inversus totalis. Five novel ZIC3 mutations in three classic heterotaxy kindreds and two sporadic CHD cases were identified. None of these alleles was found in 97 ethnically matched control samples. On the basis of these analyses, we conclude that the phenotypic spectrum of ZIC3 mutations should be expanded to include affected females and CHD not typical for heterotaxy. This screening of a cohort of patients with sporadic heterotaxy indicates that ZIC3 mutations account for approximately 1% of affected individuals. Missense and nonsense mutations were found in the highly conserved zinc finger-binding domain and in the N-terminal protein domain. Functional analysis of all currently known ZIC3 point mutations indicates that mutations in the putative zinc finger DNA binding domain and in the N-terminal domain result in loss of reporter gene transactivation. It is surprising that transfection studies demonstrate aberrant cytoplasmic localization resulting from mutations between amino acids 253-323 of the ZIC3 protein, indicating that the pathogenesis of a subset of ZIC3 mutations results at least in part from failure of appropriate nuclear localization. These results further expand the phenotypic and genotypic spectrum of ZIC3 mutations and provide initial mechanistic insight into their functional consequences.
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PMID:Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects. 1468 28

Cardiac malformations due to aberrant development of the atrioventricular (AV) valves are among the most common forms of congenital heart disease. At localized swellings of extracellular matrix known as the endocardial cushions, the endothelial lining of the heart undergoes an epithelial to mesenchymal transition (EMT) to form the mesenchymal progenitors of the AV valves. Further growth and differentiation of these mesenchymal precursors results in the formation of portions of the atrial and ventricular septae, and the generation of thin, pliable valves. Gata4, which encodes a zinc finger transcription factor, is expressed in the endothelium and mesenchyme of the AV valves. Using a Tie2-Cre transgene, we selectively inactivated Gata4 within endothelial-derived cells. Mutant endothelium failed to undergo EMT, resulting in hypocellular cushions. Mutant cushions had decreased levels of Erbb3, an EGF-family receptor essential for EMT in the atrioventricular cushions. In Gata4 mutant embryos, Erbb3 downregulation was associated with impaired activation of Erk, which is also required for EMT. Expression of a Gata4 mutant protein defective in interaction with Friend of Gata (FOG) cofactors rescued the EMT defect, but resulted in a decreased proliferation of mesenchyme and hypoplastic cushions that failed to septate the ventricular inlet. We demonstrate two novel functions of Gata4 in development of the AV valves. First, Gata4 functions as an upstream regulator of an Erbb3-Erk pathway necessary for EMT, and second, Gata4 acts to promote cushion mesenchyme growth and remodeling.
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PMID:Development of heart valves requires Gata4 expression in endothelial-derived cells. 1691

Missense, frameshift and nonsense mutations in the zinc finger transcription factor ZIC3 cause heterotaxy as well as isolated congenital heart disease. Previously, we developed transactivation and subcellular localization assays to test the function of ZIC3 point mutations. Aberrant cytoplasmic localization suggested that the pathogenesis of ZIC3 mutations results, at least in part, from failure of appropriate cellular trafficking. To further investigate this hypothesis, the nucleocytoplasmic shuttling properties of ZIC3 have been examined. Subcellular localization assays designed to span the entire open-reading frame of wild-type and mutant ZIC3 proteins identified the presence of nucleocytoplasmic transport signals. ZIC3 domain mapping indicates that a relatively large region containing the zinc finger binding sites and a known GLI interacting domain is required for transport to the nucleus. Site-directed mutagenesis of critical residues within two putative nuclear localization signals (NLSs) leads to loss of nuclear localization. No further decrease was observed when both NLS sites were mutated, suggesting that mutation of either NLS site is sufficient for loss of importin-mediated nuclear localization. Additionally, we identify a cryptic CRM-1-dependent nuclear export signal (NES) within ZIC3, and identify a mutation within this region in a patient with heterotaxy. These results provide the first evidence that control of cellular trafficking of ZIC3 is critical for function and suggest a possible mechanism for transcriptional control during left-right patterning. Identification of mutations in mapped NLS or NES domains in heterotaxy patients demonstrates the functional importance of these domains in cardiac morphogenesis and allows for integration of structural analysis with developmental function.
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PMID:Nuclear import and export signals are essential for proper cellular trafficking and function of ZIC3. 1718 87

GATA5 is a member of the zinc finger transcription factor GATA family (GATA1-6) that plays a wide variety of roles in embryonic and adult development. Experiments in multiple model systems have emphasized the importance of the GATA family members 4-6 in the development of the endoderm and mesoderm. Yet despite overlapping expression patterns, there is little evidence of an important role for GATA5 in mammalian cardiac development. We have generated a new Gata5 mutant allele lacking exons 2 and 3 that encodes both zinc finger domains (Gata5(tm)(2)(Eem)), and we show that although Gata5(-/-) mice are viable, Gata4(+/-)5(-/-) mutants die at mid-gestation and exhibit profound cardiovascular defects, including abnormalities of cardiomyocyte proliferation and cardiac chamber maturation. These results demonstrate functional redundancy between Gata4 and Gata5 during cardiac development and implicate Gata5 as a candidate modifier gene for congenital heart disease.
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PMID:Gata4 and Gata5 cooperatively regulate cardiac myocyte proliferation in mice. 1988 36

Abro1 (also known as KIAA0157) is a scaffold protein that recruits polypeptides to assemble the BRISC (BRCC36-containing isopeptidase complex) deubiquitinating (DUB) enzyme. The four subunits of BRISC enzyme include Abro1, NBA1, BRE, and BRCC36 proteins. The DUB activity of the BRISC enzyme is exclusively directed against Lys63-linked polyubiquitin that does not have a proteolytic role but regulates protein function. In this report, we identified Abro1 as a specific interactor of THAP5, a zinc finger transcription factor that is involved in G2/M control and apoptosis. Abro1 was predominantly expressed in the heart and its protein level was regulated following experimentally induced myocardial ischemia/reperfusion (MI/R) injury. Furthermore, in patients with coronary artery disease (CAD), there was a dramatic increase in Abro1 protein level in the myocardial infarction (MI) area. Increase in Abro1 leads to a significant reduction in Lys63-linked ubiquitination of specific protein targets. Reducing the Abro1 protein level exacerbated cellular damage and cell death of cardiomyocytes due to MI/R injury. Additionally, overexpression of Abro1 in a heterologous system provided significant protection against oxidative stress-induced apoptosis. In conclusion, our results demonstrate that Abro1 protein level substantially increases in myocardial injury and coronary artery disease and this up-regulation is part of a novel cardioprotective mechanism. In addition, our data suggest a potential new link between Lys63-specific ubiquitination, its modulation by the BRISC DUB enzyme, and the development and progression of heart disease.
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PMID:Regulation of Abro1/KIAA0157 during myocardial infarction and cell death reveals a novel cardioprotective mechanism for Lys63-specific deubiquitination. 2119 82

Ventricular septal defect (VSD) is the most prevalent type of congenital heart disease and a major cause for the significantly increased morbidity and mortality among infants. Aggregating evidence indicates that genetic defects are involved in the pathogenesis of congenital VSD. Nevertheless, VSD is genetically heterogeneous, and the genetic determinants for VSD in the majority of patients remain to be identified. In this study, the entire coding region of GATA4, a gene encoding a zinc finger transcription factor essential for normal cardiac morphogenesis, was sequenced in 160 unrelated patients with VSD. The available relatives of the index patient harboring the identified mutation and 200 unrelated control individuals were subsequently genotyped. The disease-causing potential of a sequence alteration was evaluated by MutationTaster, and the functional effect of the mutation was characterized using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 variation, p.R43W, was identified in a proband with VSD, that was absent in control subjects. Genetic analysis of the family members of the variation carrier showed that the substitution co-segregated with VSD. The p.R43W variant was predicted to be a pathogenic mutation, and the functional analysis demonstrated that the GATA4 R43W mutant protein resulted in significantly decreased transcriptional activity compared with its wild-type counterpart. The findings expand the mutational spectrum of GATA4 linked to VSD and provide more insight into the molecular mechanism of VSD.
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PMID:A novel GATA4 loss-of-function mutation associated with congenital ventricular septal defect. 2210 36

GATA-4, a zinc finger transcription factor, plays a critical role in heart development. Previous studies have shown that p300-targeted GATA-4 acetylation increases GATA-4 stability and transcriptional activity, which then stimulates hypertrophy of cardiomyocyte. Erythropoietin (EPO), an essential hypoxia-induced hormone for normal erythropoiesis, is known to exert cardioprotective effects against heart disease of either ischemic or non-ischemic origins. Although, various action mechanisms of EPO have been proposed in the diseased heart, its action mechanism in normal condition has not been investigated. In this study, we aimed to investigate the influence of EPO-induced ERK signaling on the regulation of GATA-4 protein action. EPO treatment increased the protein level of endogenous GATA-4 via ERK signaling pathway. Inhibition of ERK activity by U0126, suppressed EPO-induced expression of GATA-4 protein in rat cardiac myocytes. In addition, ERK activation by over-expression of constitutively active MEK1 strongly increased GATA-4 phosphorylation and subsequently enhanced its acetylation in P19 cells. EPO-induced ERK activation further increased the association of GATA-4 with p300. On the other hand, knock-down of p300 using siRNA diminished ERK-induced GATA-4 acetylation. As EPO-induced GATA-4 phosphorylation via ERK signaling pathway directly correlated with GATA-4 acetylation, we investigated to identify the ERK-dependent phosphorylation sites in GATA-4. Site-directed mutagenesis implicated that Ser-261 in GATA-4 played an important role for ERK-mediated GATA-4 acetylation. Taken together, these results indicated that EPO-induced ERK signaling activation increased GATA-4 phosphorylation and acetylation, partly via increase in the association between GATA-4 and p300, and these processes required the phosphorylation of GATA-4 at Ser-261 residue.
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PMID:Erythropoietin-activated ERK/MAP kinase enhances GATA-4 acetylation via phosphorylation of serine 261 of GATA-4. 2267 27


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