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Cardiovascular Research 2004 63(2):196-207; doi:10.1016/j.cardiores.2004.03.025
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Copyright © 2004, European Society of Cardiology

GATA transcription factors in the developing and adult heart

Sampsa Pikkarainen, Heikki Tokola, Risto Kerkelä and Heikki Ruskoaho*

Department of Pharmacology and Toxicology, Faculty of Medicine, Biocenter Oulu, University of Oulu, P.O. Box 5000, FIN-90014 Oulu, Finland

* Corresponding author. Tel.: +358-8-5375236; fax: +358-8-5375247. Email address: heikki.ruskoaho{at}oulu.fi

Received 8 November 2003; revised 29 February 2004; accepted 18 March 2004


   Abstract
Top
 Abstract
1. Introduction
 2. Expression pattern and...
 3. Protein structure
 4. Cardiac target genes
 5. Activity and expression...
 6. Regulatory mechanisms
 7. Interactions with cofactors...
 8. Interactions with cofactors...
 9. Future perspectives
 10. Concluding remarks
 References
 
During the past decade, emerging evidence has accumulated of different nuclear transcription factors in regulation of cardiac development and growth as well as in cardiac hypertrophy and heart failure. GATA-4, -5 and -6 are zinc finger transcription factors that are expressed in the developing heart and GATA-4 and -6 continue expression in the adult cardiac myocytes. GATA-4 and -6 regulate expression of several cardiac-specific genes, and during murine embryonic development, GATA-4 is essential for proper cardiac morphogenesis. In support of this, mutations of gene for GATA-4 or for its cofactors have been associated with human congenital heart disease. Pressure overload of the heart in vivo as well as hypertrophic stimulation of cardiac myocytes in vitro provide adequate stimulus for activation of GATA-4. Activity of GATA-4 transcription factor is subject to regulation at the level of gene expression and through post-translational modifications of GATA-4 protein. A number of genes induced during cardiac hypertrophy possess functional GATA sites in their promoter region and cardiac-specific overexpression of GATA-4 or -6 leads to cardiac hypertrophy. In addition, a pattern of interactions between GATA-4 and its numerous cofactors have been identified, showing an increasing complexity in regulatory mechanisms. The present review discusses current evidence of the role and regulation of GATA transcription factors in the heart, with an emphasis in the GATA-4 and development of cardiac hypertrophy.

KEYWORDS GATA-4; GATA-6; Transcription factor; Mitogen-activated protein kinase; Signal transduction; Cardiac hypertrophy; Heart failure


   1. Introduction
Top
 Abstract
 1. Introduction
2. Expression pattern and...
 3. Protein structure
 4. Cardiac target genes
 5. Activity and expression...
 6. Regulatory mechanisms
 7. Interactions with cofactors...
 8. Interactions with cofactors...
 9. Future perspectives
 10. Concluding remarks
 References
 
Intracellular signals converge on a limited number of regulatory elements to regulate expression of individual genes. Thus, transcription factors that regulate expression of other genes in embryonic and/or adult heart may constitute a point of signal convergence for various stimuli. The family of GATA transcription factors regulate differentiation, growth and survival of a wide range of cell types (for reviews see Refs. [1–6]). This review summarizes recent advances in understanding the role and modulation of GATA transcription factors in the heart, focusing especially on GATA-4 and on the development of pathological cardiac hypertrophy.


   2. Expression pattern and cardiogenesis
Top
 Abstract
 1. Introduction
 2. Expression pattern and...
3. Protein structure
 4. Cardiac target genes
 5. Activity and expression...
 6. Regulatory mechanisms
 7. Interactions with cofactors...
 8. Interactions with cofactors...
 9. Future perspectives
 10. Concluding remarks
 References
 
The family of GATA transcription factors consists of six proteins (GATA-1–6). GATA-1–2–3 are important regulators of hematopoietic stem cells and their derivatives [1–4], whereas GATA-4, -5, and -6 genes are expressed in various mesoderm and endoderm-derived tissues [7–10]. GATA-4 exhibits a developmentally regulated and tissue-specific expression pattern in mice, and during embryonic and fetal development GATA-4 mRNA is found in the heart, gut, gonads, liver, visceral endoderm and parietal endoderm [7,8]. Interestingly, GATA-4 is one of the earliest transcription factors expressed in developing murine cardiac cells [11]. Specifically, GATA-4 mRNA can be detected as early as at 7.0–7.5 days postcoitum (dpc) in the precardiac mesoderm and both the transcript and protein are found during formation and bending of the heart tube (8.0 dpc) in endocardium, myocardium and precardiac mesoderm [11]. Abundant GATA-4 mRNA continues to be expressed in cardiac myocytes throughout the life of the animal [7,11]. In adult mouse, GATA-4 transcript is additionally found in gonads, lung, liver and small intestine [7]. In contrast, GATA-5 is detected during embryonic development in heart, lungs, urogenital ridge, bladder and epithelium of the gut and, during adulthood, in gastrointestinal tract, bladder, lungs and endocardium, but not in myocardium [10,12]. GATA-6 mRNA is expressed during embryonic and fetal development in visceral endoderm, heart, lungs, urogenital ridge, vascular smooth muscle cells, and in gastrointestinal tract and, in adults, it is detected in myocardium, aorta, gastrointestinal tract and to a lesser extent in the liver and lungs [10].

After the initial studies identifying GATA-4 as a major GATA-binding factor in the developing heart, its role during development has emerged. In P19 embryonal carcinoma cells, overexpression of GATA-4 increases differentiation of beating cardiocytes, while inhibition of GATA-4 by antisense strategy prevents cardiocyte differentiation and triggers extensive apoptosis [13,14]. GATA-4 deficient embryonic stem (ES) possess potential, though reduced, to differentiate into cardiac myocytes in vitro [15], and are partially defective in their ability to generate proper visceral endoderm and definitive endoderm of the foregut [16,17]. Notably, transgenic mice with inactivation of the GATA-4 gene die during embryonic development due to the failure of ventral morphogenesis and heart tube formation between 8.0 and 9.0 dpc [18,19]. In GATA-4 deficient mice the differentiation of cardiac myocytes is not impaired and cardiac atrial natriuretic peptide (ANP) and {alpha}-myosin heavy chain ({alpha}-MHC) genes are normally expressed, suggesting that upregulation of endogenous GATA-6 mRNA is potentially compensating the lack of GATA-4 [18,19]. The defect of cardiogenesis in GATA-4 deficient mice may result from an early endodermal defect: abnormal differentiation and ventral migration of endodermal cells prevents concomitant movement of myocardial cells leading to cardia bifida (for review see Ref. [20]). GATA-6 deficient mice die shortly after implantation (at 5.5–7.5 dpc) due to abnormal visceral endoderm function and defects in extraembryonic tissue [21]. In addition, the lack of GATA-6 appears to prevent generation of endodermally derived bronchial epithelium [22]. In embryoid bodies derived from GATA-6 deficient ES cells, abnormal differentiation is accompanied by attenuated levels of GATA-4 mRNA, suggesting that GATA-6 may regulate the expression of GATA-4 during differentiation [22]. Taken together, the expression of GATA-4 appears to be indispensable for proper endodermal differentiation and ventral morphogenesis, but not necessarily for differentiation of cardiac myocytes, in which GATA-6 may be capable of replacing GATA-4.


   3. Protein structure
Top
 Abstract
 1. Introduction
 2. Expression pattern and...
 3. Protein structure
4. Cardiac target genes
 5. Activity and expression...
 6. Regulatory mechanisms
 7. Interactions with cofactors...
 8. Interactions with cofactors...
 9. Future perspectives
 10. Concluding remarks
 References
 
A characteristic feature of GATA factors is a domain of two adjacent zinc fingers (Cys-X2-Cys-X17-Cys-X2-Cys) that directs preferential binding to the nucleotide sequence element 5'-(A/T)GATA(A/G)-3' of target gene promoters [23]. GATA-4, -5 and -6 share a high homology (~80–90%) in the amino acid sequence within the two zinc fingers and the DNA sequence recognition domain of the C-terminal zinc finger is well-conserved among all GATA proteins [7,9,10,24–26]. Given the homology of DNA binding domains between different GATA factors, the solution structure of GATA-1 bound to DNA may elucidate also DNA binding mechanisms of GATA factors in general. According to the solution structure of C-terminal zinc finger of GATA-1 bound to DNA, N-terminal and central part of GATA DNA binding domain contact with major groove of DNA and C-terminal region interacts with minor groove [27]. Omichinski et al. [27] elucidated the three-dimensional aspects of this interaction, suggesting that the complex resembles a hand holding a rope with the palm and fingers representing the protein core and the thumb, the carboxyterminal tail. Similar to GATA-1, domain deletion analysis of GATA-4 protein demonstrates that the C-terminal zinc finger is sufficient and necessary for DNA binding [28]. N-terminal zinc finger, which is unable to bind DNA by itself, influences stability and specificity of DNA binding as well as transcriptional activation by GATA factors [29,30]. Most of the protein–protein interactions of GATA factors are mediated by its C-terminal zinc finger, while N-terminal zinc finger interacts with Friend of GATA (FOG) transcription factors (see below). In addition, deletion analysis of GATA-4 shows that a nuclear localization sequence (NLS) is present within the basic domain adjacent to the C-terminal zinc finger and two separate transcriptional activation domains are present within the N terminus of the protein [28] (Fig. 1). In comparison with GATA-5 and -6 these activation domains are partially conserved [7,9,10], which may explain some functional redundancy and the similarities with GATA-4 in transcriptional activation mechanisms.


Figure 1
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  		Fig. 1 Protein structure of murine GATA-4. Transcriptional activation domains are marked with red, zinc finger domains with blue and domain for nuclear localization with green. Ser-105 is a phosphorylation target for mitogen-activated protein kinases (MAPK) and Ser-261 for protein kinase A (PKA). Single amino acid mutations V217G and G295S abolish interaction with Friend of GATA-2 (FOG-2) and TBX-5, respectively.

 

   4. Cardiac target genes
Top
 Abstract
 1. Introduction
 2. Expression pattern and...
 3. Protein structure
 4. Cardiac target genes
5. Activity and expression...
 6. Regulatory mechanisms
 7. Interactions with cofactors...
 8. Interactions with cofactors...
 9. Future perspectives
 10. Concluding remarks
 References
 
Accumulating evidence underscores the role of GATA-binding motifs in enhancer region of several cardiac-specific genes. GATA binding elements of rat {alpha}-MHC promoter are required for activity of the promoter in the heart, and {alpha}-MHC promoter can be activated in skeletal muscle by co-transfection of GATA-4 expression plasmid [31]. Also, other sarcomeric genes, such as cardiac troponin C and I and myosin light chain-3, show a myocyte-enriched expression pattern, at least in part, due to GATA elements in the promoter region [32–36]. In addition to the sarcomeric proteins, also genes for ANP, BNP and corin, a cardiac enzyme involved in the processing of natriuretic peptides, and multiple other genes including Na+/Ca2+-exchanger, acetylcholine receptor-M2, cardiac-restricted ankyrine repeat protein (CARP), adenosine receptor-A1 and carnitine palmitoyltransferase-1β can be induced by GATA-4 [37–46]. Notably, genes of transcription factors that regulate developmental expression pattern in vivo contain GATA motifs in their promoter region: in the context of gene for dHAND transcription factor, two conserved GATA elements are essential for right ventricle-specific activity of the promoter during murine embryogenesis [47]. Murine Nkx-2.5 gene promoter contains two GATA elements, which bind GATA-4 and are necessary for the promoter activity in the heart, pharynx and spleen at the early stages of embryogenesis [48,49]. Interestingly, murine GATA-6 gene contains an Nkx-2.5 binding element (NKE), which is essential for cardiac-specific expression of the promoter during cardiogenesis [50], suggesting a reinforcing network of GATA factors and their cofactors at the level of gene expression. Adenovirally delivered GATA-4 or GATA-6 antisense cDNA treatment of neonatal rat cardiac myocytes results in an inhibition of cardiac-restricted gene expression, including BNP, β-MHC and cardiac troponin I, while only diminution of GATA-4 attenuates {alpha}-MHC, which is probably related to lower affinity of GATA-6 on GATA site of {alpha}-MHC promoter [51]. However, high levels of GATA-4 are found in other tissues than the heart, such as gonads [52,53], and thus additional mechanisms likely contribute to the cardiac expression of these genes. Given that GATA-4 induces several cardiac-specific promoters that are activated during both in cardiogenesis and cardiac hypertrophy, GATA motifs of cardiac gene promoters may have an important role in these processes. In support of this hypothesis, full induction of β-MHC or angiotensin II type 1 receptor (AT1) genes in pressure-overloaded rat hearts requires intact GATA binding elements in the promoter regions [54,55]. Furthermore, functional GATA elements of gene promoters are required for the activation of adenylosuccinate synthetase-1 transcription by pacing in neonatal rat cardiac myocytes [56] and for rat BNP promoter induction in the hearts of nephrectomized rats [57]. GATA binding sites are necessary for phenylephrine (PE) induced rat preproendothelin [58] as well as isoproterenol (ISO) or PE induced human BNP promoter [59,60] activities in neonatal rat cardiac myocytes. Endothelin-1 (ET-1) induces ANP and human BNP promoter activities [61,62] in a GATA-site dependent manner. In the context of rat BNP promoter, GATA sites are required for transcriptional induction in mechanically stretched or lipopolysaccharide stimulated neonatal rat cardiac myocytes [63,64]. Interestingly, it is possible that reinforcing loops may further amplify GATA-4 and/or GATA-6 signaling during cardiomyocyte differentiation and/or hypertrophy: once activated, GATA-4/-6 increase transcription of bone morphogenetic protein-4 (BMP-4) [12] and preproendothelin [58] via binding on GATA sites of their promoters, and in turn, BMPs and ET-1 are activators of GATA-4 [65,66].


   5. Activity and expression of GATA-4 in hypertrophied cardiomyocytes
Top
 Abstract
 1. Introduction
 2. Expression pattern and...
 3. Protein structure
 4. Cardiac target genes
 5. Activity and expression...
6. Regulatory mechanisms
 7. Interactions with cofactors...
 8. Interactions with cofactors...
 9. Future perspectives
 10. Concluding remarks
 References
 
The data on cis regulatory elements and trans-acting factors responsible for expression of GATA factors in cardiac myocytes is limited to GATA-6. 5' Flanking region of the mouse GATA-6 gene contains several potential consensus sites for Sp1 transcription factor (GC boxes), a number of GATA elements, two E-box elements and NKE, but no elements for serum response factor (SRF), myocyte enhancer factor-2 (MEF-2) or transcription enhancer factor-1 (TEF-1). While Nkx-2.5 is able to transactivate the GATA-6, other potential cardiac transcription factors, including MEF-2C and -2B, SRF, eHAND, dHAND, and TEF-1, do not activate GATA-6 promoter in vitro [50]. Therefore, the precise molecular mechanisms regulating the transcription of GATA factors in response to hypertrophic stimuli are currently unknown.

Cumulative evidence suggests that GATA-4 DNA binding activity increases during initiation of hypertrophic response of cardiac myocytes in vitro and in vivo. Importantly, rats infused with arginine8-vasopressine (AVP) demonstrate substantial pressure overload together with activation of GATA-4 DNA binding in ventricles, which can be blocked with bosentan, a mixed ETA/B receptor antagonist [66]. In perfused isolated rat hearts, mechanical loading activates GATA-4 binding through endogenous ET-1 and angiotensin II (Ang II), and infusion of either of the substances is sufficient to induce GATA-4 DNA binding activity [67]. In addition, various hypertrophic agonists and cyclic mechanical stretch activate GATA-4 DNA binding in cultured cardiac myocytes [63,68–73]. The early activation of GATA-4 DNA binding is rapid in stretched and pressure-overloaded rat hearts and peaks at 30 min [66,67], which is similar in ET-1 (at 30 to 60 min [73]) and ISO (at 30 min [69]) stimulated or mechanically stretched (at 60 min [63]) neonatal rat cardiac myocytes. In immortalized adult mouse atrial myocyte cell line (HL-1 [74]), activation of GATA-4 DNA binding peaks even more rapidly (at 10 min) by the treatment with ET-1 or phorbol-12-myristate-13-acetate (PMA) [70,71], but is maximal at 30 min in Ang II stimulated cells [75]. In addition, significant induction of cardiac GATA-4 DNA binding activity is detected in bilaterally nephrectomized rats with robust hemodynamic overload at 26–28 h [57] and in aortic banded rats at 2 days [54]. Taken together, GATA-4 DNA binding both in vitro and in vivo is initially activated with relatively early time-course, and it may additionally increase with a sustained time course in overloaded myocardium in vivo.

The studies regarding the regulation of GATA-4 activity at the mRNA or protein levels have produced variable results depending on the hypertrophic stimulus. GATA-4 mRNA levels are not altered in isolated perfused rat hearts by ventricular stretch (at 15 min to 2 h [67]) or in the hearts of AVP infused (at 15 min to 4 h [66]) or nephrectomized rats [57]. Similarly, GATA-4 mRNA levels remain stable in cultured neonatal rat cardiac myocytes treated with ET-1 (from 0.5 to 4 h [66]). Therefore, given that AVP infusion activates GATA-4 DNA binding via ET-1 and neither AVP infusion in vivo or ET-1 treatment in vitro have effect on GATA-4 gene expression, at least the ET-1-dependent induction of GATA-4 DNA binding does not require increased synthesis or stabilization of GATA-4 mRNA. Accordingly, protein levels of GATA-4 or GATA-6 in neonatal rat cardiac myocytes were not affected by treatment with PE [68,76]. In contrast, mechanical stretch (at 4 h [63]), pacing (from 1 to 12 h [56]) and ISO (from 6 to 12 h [69]) transiently elevate GATA-4 mRNA levels in neonatal rat cardiac myocytes. Infusion of ISO, PE or both in adult mice increases cardiac GATA-4 and Nkx-2.5 mRNA levels from 3rd day to at least for 2 weeks [77]. In this model, normalization of blood pressure with hydralazine is not sufficient to prevent upregulation of GATA-4 mRNA levels or the increase in cardiac mass, while 1 week after withdrawal of the infusions the levels of GATA-4 mRNA return to baseline together with normalization of cardiac index [77]. In addition, pressure overload of the right ventricle in pulmonary artery banded rats increases protein levels of GATA-4 and some of its cofactors including Nkx-2.5, MEF-2 and dHAND [78]. Collectively, it appears that GATA-4 gene may be regulated at the level of transcription and/or transcript stability in certain experimental rodent models of cardiac hypertrophy. Since the early activation of GATA-4 DNA binding peaks hours prior to possible increase in GATA-4 mRNA levels, additional mechanisms are likely to be involved.


   6. Regulatory mechanisms
Top
 Abstract
 1. Introduction
 2. Expression pattern and...
 3. Protein structure
 4. Cardiac target genes
 5. Activity and expression...
 6. Regulatory mechanisms
7. Interactions with cofactors...
 8. Interactions with cofactors...
 9. Future perspectives
 10. Concluding remarks
 References
 
GATA-4 protein is subject to post-translational modifications, which affect its DNA binding activity, transactivation and/or localization within cardiac myocytes (Fig. 2). Treatment of neonatal rat cardiac myocytes with ET-1, PE or ISO increases GATA-4 phosphorylation [69,72,76,79,80], which is accompanied by an increase in GATA-4 DNA binding activity [72,76,80]. Similarly, ET-1 and PMA induce phosphorylation of GATA-4 in HL-1 cells [70,71]. In murine GATA-4, one key amino acid for phosphorylation is Ser-105. Studies using fusion protein of GATA-4 activation domain (amino acids 33–227) with intact or mutated Ser-105 linked to GAL4 DNA binding domain show that Ser-105 is required for GATA-4-mediated transcriptional activation [80]. In addition, despite not being located within the DNA binding domain of GATA-4, mutation of Ser-105 reduces the DNA binding activity [80]. It has also been suggested that phosphorylation of GATA-4 on Ser-105 may increase its stability within the cells [81].


Figure 2
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  		Fig. 2 Schematic presentation of potential signal transduction mechanisms converging on GATA-4 and its cofactors. Ang II, angiotensin II; CaMK, calcium-calmodulin dependent kinase; CN, calcineurin; ERK, extracellular signal-regulated kinase; ET-1, endothelin-1; GPCR, G-protein coupled receptor; GSK-3, glycogen synthase kinase-3β; HDAC, histone deacetylase; ISO, isoproterenol; MAPK, mitogen-activated protein kinase; MEF-2, myocyte enhancer factor-2; MEK1, MAPK or ERK kinase-1; NFAT, nuclear factor of activated T-cells; PE, phenylephrine; PI3K, phosphatidylinositol 3-kinase; ROCK, Rho-associated coiled-coil forming kinase; SRF, serum response factor.

 
Kinases shown to catalyze Ser-105-specific phosphorylation of GATA-4 in cardiac myocytes are extracellular signal-regulated kinase (ERK) [80] and p38 mitogen-activated protein kinase (p38 MAPK) [79], two members of the MAPK family (for review see Ref. [82]). GATA-4 has been identified as a target for small GTPase RhoA activated p38 MAPK resulting in phosphorylation of Ser-105 of GATA-4 protein [79]. ERK may mediate phosphorylation of Ser-105 of GATA-4 protein in response to PE treatment of cardiac myocytes [80]. Moreover, an inhibitor (Y-27632) against a downstream kinase of RhoA (Rho-associated coiled-coil forming kinase (ROCK)), prevents both PE-induced increase in ERK phosphorylation and GATA-4 DNA binding activity [83]. In cultured pulmonary artery smooth muscle cells, serotonin activates GATA-4 via similar mechanism including MEK/ERK-mediated induction of GATA-4 DNA binding activity [84]. However, there is evidence suggesting that in neonatal rat cardiac myocytes ERK may function as a regulator of basal GATA-4 DNA binding activity, while p38 MAPK may mediate activation of GATA-4 by ET-1 [72]. Given that ET-1 activates both p38 and ERK and they are able to phosphorylate Ser-105 of GATA-4, it is not clear which are the additional mechanisms that modify activation of GATA-4 and consequent gene expression. Also, the physiological role of this functional redundancy is unknown. Of note, in addition to Ser-105, GATA-4 protein [7] contains at least 6 other potential targets for MAPK mediated Ser-phosphorylation that could be involved in regulation of GATA-4 DNA binding and GATA-dependent transcription. In addition, ET-1 and MAPKs activate several other nuclear mediators than GATA-4, such as ETS-like gene-1 (Elk-1) and nuclear factor of activated T-cells (NFAT), that are involved in regulation of hypertrophic program of cardiac myocytes [85,86]. Cardiac-specific activation of ERK or p38 MAPK pathways appear to induce compensated cardiac hypertrophy [87] or restrictive cardiomyopathy [88], respectively. In view of these transgenic murine models of GATA-4 regulating pathways, it is apparent that partially overlapping regulation of GATA-4 is further modified in the nucleus by other MAPK-dependent mechanisms and nuclear effectors.

In addition to p38 MAPK and ERK, GATA-4 has been shown to be target of glycogen synthase kinase-3β (GSK-3β). Recent evidence shows that GSK-3β functions as an important negative regulator of cardiac hypertrophy (for review see Ref. [89]). GSK-3β is negatively regulated by protein kinase B (PKB)/Akt, a major kinase downstream from phosphatidylinositol 3-kinase (PI3K). Therefore, stimuli that activate PI3K inhibit GSK-3β through PKB/Akt. GATA-4 interacts physically with GSK-3β, which phosphorylates N-terminal domain of GATA-4 protein (within 2–205 amino acids). The increased phosphorylation inhibits GATA-4-dependent transcription, at least in part, by decreasing nuclear levels of GATA-4 protein via a nuclear exportin Crm1 [69]. Moreover, inactivation of GSK-3β correlates with levels of nuclear translocation of NFAT, a cofactor of GATA-4 [90]. Hence, GSK-3β may act in parallel with the MAPKs to regulate GATA-4 dependent gene expression and growth of cardiac myocytes.

Of note, at least in gonadal cells (MA-10 mouse Leydig tumor cell line), dibuturyl cAMP treatment increases phosphorylation of GATA-4 via protein kinase A (PKA) at evolutionary conserved Ser-261, which is located between the two zinc finger domains of GATA-4 [91]. GATA-4 phosphorylation by PKA leads to recruitment of transcriptional co-activator, cAMP responsive element-binding protein-binding protein (CBP), and synergistic transcriptional activation [91]. While CBP is capable to stimulate transcription by GATA-4 in transiently transfected NIH3T3 cells [92], it remains to be addressed whether similar PKA dependent phosphorylation mechanism regulates GATA-4 in cardiac myocytes.

Besides phosphorylation, GATA-4 activity can be further influenced by other posttranslational modifications, such as acetylation. Like CBP its close relative p300 possesses intrinsic histone acetyltransferase activity that is required for the synergistic transcriptional activation caused by interaction of GATA-4 with p300/CBP [93]. However, contradicting data exists whether p300/CBP directly acetylates GATA-4. While p300 overexpression failed to acetylate lysine residues of GATA-4 in NIH3T3 cells [93] similar experiments in COS7 cells revealed clear acetylation of GATA-4 [94]. Recent evidence shows that GATA-4 may be regulated via acetylation in cardiac myocytes during hypertrophic growth process, possibly in a p300-dependent mechanism. PE increases p300 expression as well as levels of acetylated GATA-4 in cultured neonatal rat ventricular myocytes [94]. Further, transgenic mice with cardiac-restricted overexpression of p300 develop cardiac hypertrophy, which is associated with increased GATA-4 acetylation and DNA binding activity [94].


   7. Interactions with cofactors in developing heart
Top
 Abstract
 1. Introduction
 2. Expression pattern and...
 3. Protein structure
 4. Cardiac target genes
 5. Activity and expression...
 6. Regulatory mechanisms
 7. Interactions with cofactors...
8. Interactions with cofactors...
 9. Future perspectives
 10. Concluding remarks
 References
 
GATA-4 has been shown to cooperate with a number of other transcription factors and co-activators in vitro [37,51,61,93,95–106]. Specifically, the C-terminal zinc finger domain of GATA-4 that is required for DNA binding has been found to interact physically with several transcription factors and co-activators in regulation of cardiac gene promoters. However, a co-repressor protein FOG-2 interacts with N-terminal zinc finger of GATA-4, and GATA-6 may require both zinc fingers of GATA-4 for their interaction. While the physical interaction with cofactors requires intact zinc finger domains, the synergistic transcriptional activation appears to require intact N-terminal and/or C-terminal activation domains of GATA-4 (see Table 1). There is evidence that some of the interactions of GATA-4 may occur simultaneously with or even through p300/CBP to regulate transcriptional activation, including those with dHAND [95], retinoid X receptor-{alpha} (RXR{alpha}) [105], and Yin Yang-1 [107]. In addition, GATA-4, SRF and Nkx-2.5 may generate complex for synergistic transactivation of genes [108,109]. Interestingly, transgenic mice with a single amino acid substitution on GATA-4 protein (V217G), which abolishes interaction with FOG-2, have phenotypical similarities to transgenic mice lacking the FOG-2 gene, such as absence of coronary vasculature and defects in septation, suggesting that this interaction is indispensable for proper heart morphogenesis and coronary vascular development [110]. In human, mutations of Nkx-2.5 gene associate with development of congenital heart disease including cardiac septal defects and atrioventricular conduction abnormalities [111,112]. These mutations alter Nkx-2.5 DNA binding activity [111]. In addition, the mutant Nkx-2.5 proteins and GATA-4 show abnormal ANP promoter transactivation, suggesting that interaction with GATA-4 may play a role in the development of the cardiac phenotype [113]. Impaired synergistic transcriptional activation by Nkx-2.5 and TBX-5, a member of T-box transcription factor family, is detected, in turn, with some of the mutations of TBX-5 gene that are associated with Holt-Oram syndrome [114]. Holt-Oram syndrome is an autosomal dominant syndrome characterized by cardiac septation defects and upper extremity skeletal abnormalities (for review see Ref. [115]). Notably, GATA-4 haploinsufficiency is associated with congenital heart defects in patients with 8p23.1 monosomy [116]. Garg et al. [117] have recently provided a potential linkage for a phenotypic similarity (atrial septal defects) resulting from TBX-5 or GATA-4 haploinsufficiency: mutation of human GATA-4 gene resulting in a Gly to Ser substitution at codon 296 (adjacent to NLS and C-terminal zinc finger) is associated with cardiac septal defects. This mutation (mouse orthologue at codon 295) decreases GATA-4 DNA binding activity and abrogates physical association with TBX-5, but not with Nkx-2.5 [117]. Moreover, a frame-shift mutation of human GATA-4 gene resulting in truncation of the last 40 amino acids of the protein is associated with atrial septal defects [117]. This mutation, in turn, renders GATA-4 transcriptionally inactive and likely haploinsufficient [117]. Taken together, cardiac malformations that associate with mutations of GATA-4, Nkx-2.5 or TBX-5 genes may be in part due to disruption of their combinatorial interactions.


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  		Table 1 Summary for interactions of GATA-4 and its cofactors

 

   8. Interactions with cofactors in hypertrophied cardiomyocytes
Top
 Abstract
 1. Introduction
 2. Expression pattern and...
 3. Protein structure
 4. Cardiac target genes
 5. Activity and expression...
 6. Regulatory mechanisms
 7. Interactions with cofactors...
 8. Interactions with cofactors...
9. Future perspectives
 10. Concluding remarks
 References
 
Potential role of the interactions between GATA-4 and its cofactors during cardiac hypertrophy is supported by circumstantial evidence. In support of a multiple line of evidence that GATA-4 has a role in cardiac hypertrophy, overexpression of GATA-4 or GATA-6 activates hypertrophic growth in cultured rat neonatal cardiac myocytes and in the hearts of transgenic mice [68]. To examine the role GATA-4 DNA binding in ET-1 stimulated neonatal rat cardiac myocytes, GATA decoy oligonucleotides have been used to competitively inhibit binding activity on GATA-elements of target promoters [73]. GATA decoy oligonucleotide treatment decreases basal cardiac gene expression (i.e. ANP and BNP) to similar extent as seen with adenoviral antisense strategy, but in contrast, is insufficient to affect ET-1 induced protein synthesis, hypertrophic morphology or natriuretic peptide gene expression [73]. In contrast, depletion of GATA-4 protein in cultured neonatal cardiac myocytes by adenoviral antisense strategy inhibits hypertrophy of neonatal rat cardiac myocytes in response to mechanical stretch, PE and ET-1 [63,79]. Differential effects of decoy oligonucleotide and adenoviral antisense treatments may be related to complex formation of GATA proteins with other transcription factors, which is likely more effectively crippled by depletion of GATA-4 protein levels than decoy oligonucleotide which blocks GATA binding on target promoters but does not necessarily affect interaction with its cofactors. Given that various hypertrophic stimuli, including ET-1, have an effect on complex formation between GATA-4 and its cofactors, the interactions may lead to transactivation of gene expression via cis-elements of the cofactors. In support of this, some cofactors of GATA-4, such as Nkx-2.5 or SRF, have been shown to be able to recruit GATA-4 to cardiac gene promoters [104,109]. In stretched neonatal rat cardiac myocytes, increase in BNP mRNA levels is completely inhibited by depletion of GATA-4 protein by GATA-4 antisense adenovirus, but in the context of BNP promoter delivered by liposome transfection, mutation of GATA elements alone inhibits stretch inducibility only by 40%. Mutation of Nkx-2.5 binding element (NKE) alone has no effect on BNP promoter activation by stretch, but when combined with mutation of GATA sites, almost completely abolishes the response, suggesting that these factors may act in concert to regulate hypertrophic gene program [63]. In addition, adenoviral overexpression of a dominant negative fusion protein composed of GATA-4 DNA binding domain and a transcriptional repressor domain of Engrailed attenuates PE induced hypertrophy of neonatal rat cardiac myocytes [68]. However, when comparing different inhibitory strategies targeted on GATA-4 activity, it should be noted that higher transfection efficiency is obtained by adenoviral than liposomal transfection and the effects on high order complex formation by either approaches remains to be determined.

A number of GATA-4's cofactors have been implicated in cardiac hypertrophy, most notably NFAT, MEF-2 and SRF. These GATA-4-interacting factors may provide a point of signal convergence for various hypertrophic stimuli and signaling mechanisms. In the heart, calcium/calmodulin complex (Ca2+/CaM) activates phosphatases, including calcineurin [101]. Activation of calcineurin by the Ca2+/CaM results in dephosphorylation of its substrates including NFAT [118]. Originally, by using GATA-4 as a bait (amino acids 130–409 fused to yeast GAL4 protein) in the yeast two-hybrid system, Molkentin et al. [101] identified NFATc4 (also called as NFAT-3) as a novel GATA-4's cofactor. Importantly, they demonstrated that either calcineurin or the nuclear localized mutant of its substrate (mutant of NFATc4) is sufficient to produce cardiac hypertrophy when overexpressed in the heart of transgenic mice [101]. Moreover, constitutively active calcineurin activates human BNP promoter synergistically with its substrate NFATc4 and GATA-4 [101], whereas inhibition of calcineurin prevents ET-1, 1% serum, Ang II or PE induced hypertrophy in vitro [119,120]. Supporting the potential role of GATA-4–NFAT interaction during hypertrophic growth, physical interaction between GATA-4 and NFATc increases in ET-1 treated neonatal rat cardiac myocytes [121]. However, while numerous transgenic animal models provide strong evidence supporting the role of calcineurin/NFAT-dependent signaling in regulation of cardiac growth (for review see Ref. [122]), pharmacological inhibitors of calcineurin have produced conflicting results in various experimental rodent models (for reviews see Refs. [123,124]).

MEF-2 transcription factor is an important downstream mediator of Ca2+/CaM dependent kinases (CaMK) and MAPKs. Increased intracellular [Ca2+] results in autophosphorylation of CaMKII, which switches it to a Ca2+-independent state and prolongs its activation. CaMKI, which is ubiquitously expressed, and CaMKIV, mainly expressed in testis and brain, are activated by upstream Ca2+/CaM dependent protein kinases [125,126]. Overexpression of CaMKII{delta}, CaMKI or CaMKIV in the heart of transgenic mice is sufficient to promote hypertrophic growth [127,128]. CaMK stimulates MEF-2 activity by dissociating class II histone deacetylases (HDACs) from the DNA-binding domain leading to nuclear export of HDAC with intracellular chaperone 14-3-3 [129]. In addition, MAPKs, which activate MEF-2 by phosphorylation of the transcription activation domain, maximally stimulate MEF-2 activity only when repression by HDACs is relieved by CaMK signaling [130]. In hematopoietic cells, the activities of GATA-1 and GATA-2 are repressed by interaction with HDACs [131,132]. It remains to be determined whether HDACs directly interact with GATA-4 in cardiac myocytes.

SRF activity is regulated by numerous mechanisms ranging from expression of SRF to RhoA dependent changes in actin dynamics, association with cofactors or chromatin remodeling of its target promoter sequences (for review see Ref. [133]). Analogically to MEF-2, CaMK dependent dissociation of HDACs activates transcriptional regulator SRF in cardiac myocytes [134]. In addition, SRF may regulate cardiac gene expression via MAPK dependent activation of ternary complex factors [135]. SRF and GATA-4 and/or -6 form a ternary complex on a 30-bp cis-element of ANP promoter containing juxtaposed GATA/SRF binding motifs, which mediates activation of ANP promoter in ET-1 stimulated neonatal cardiac myocytes [61]. Notably, cardiac-restricted overexpression of SRF results in robust cardiac hypertrophy in transgenic mice [136], indicating a potential role for SRF in the development of pathological cardiac hypertrophy. Cardiac-specific overexpression of upstream regulator RhoA results in conduction system disturbances and consequent ventricular dysfunction rather than cardiac hypertrophy [137]. Taken together, while there is cumulative evidence for the role of GATA-4's cofactors as well as GATA-4 itself in the development of pathologic cardiac hypertrophy, it remains to be addressed which of the interactions of GATA-4 are crucial in vivo.


   9. Future perspectives
Top
 Abstract
 1. Introduction
 2. Expression pattern and...
 3. Protein structure
 4. Cardiac target genes
 5. Activity and expression...
 6. Regulatory mechanisms
 7. Interactions with cofactors...
 8. Interactions with cofactors...
 9. Future perspectives
10. Concluding remarks
 References
 
Recent evidence suggests that the role of GATA transcription factors may extend to the regulation of cardiac myocyte survival. In the context of erythropoiesis, deficiency of GATA-1 gene results in a developmental growth arrest and apoptosis of erythroid precursors [138], which may be linked to GATA-dependence of anti-apoptotic Bcl-xL protein expression [139]. Similarly, inhibition of GATA-4 protein levels increases apoptosis of P19 embryonal carcinoma cells [13,14] and GATA-4 downregulation is associated with increased apoptosis in cultured mouse granulosa cells [140], while GATA-4 or GATA-6 overexpression protects cardiac myocytes from anthracycline-induced apoptosis [141]. Expression of hepatocyte growth factor (HGF), a potent mitogen for hepatocytes, is induced by the ischemia–reperfusion in rat heart [142]. Administration of recombinant HGF reduces the size of infarct area and improves cardiac function by suppressing apoptosis of cardiac myocytes in the same experimental model [143]. Interestingly, in cultured cardiac myocytes HGF increases Ser-105 phosphorylation and activation of GATA-4 protein via MEK1/ERK cascade, which results in induction of the levels of anti-apoptotic Bcl-xL protein, thus providing an interesting insight for cardioprotective actions of GATA-4 [144]. Additionally, GATA-4 is among the earliest factors known to bind the albumin gene promoter in liver precursor cells, and it accesses sites in silent chromatin via novel mechanism: GATA-4 appears to be capable of binding its site in compacted chromatin and opening the local nucleosomal domain in the absence of ATP-dependent enzymes [145]. It remains to be addressed whether GATA-4 might act as a chromatin remodeling transcription factor in the context of cardiac gene expression.


   10. Concluding remarks
Top
 Abstract
 1. Introduction
 2. Expression pattern and...
 3. Protein structure
 4. Cardiac target genes
 5. Activity and expression...
 6. Regulatory mechanisms
 7. Interactions with cofactors...
 8. Interactions with cofactors...
 9. Future perspectives
 10. Concluding remarks
References
 
In summary, GATA-4 and -6 may play an important role during early cardiac development and they may participate in the development of cardiac hypertrophy during adulthood. GATA factors appear to function as trophic nuclear factors in the postnatal heart, and while having several target genes and cofactors, the hierarchy of the regulatory mechanisms is yet to be elucidated. It will be of interest to study these mechanisms that regulate utilization of GATA factors in complexes of alternative cofactors in fetal and adult tissues as well as those that govern the balance either towards cardioprotection or detrimental cardiac hypertrophy. Furthermore, it is intriguing to speculate that specific interactions between transcription factors could provide an attractive therapeutic target in treatment of cardiovascular diseases.


   Acknowledgements
 
The original research was supported by grants from the Academy of Finland, Sigrid Juselius Foundation, Finnish Foundation for Cardiovascular Research, National Technology Center Tekes, Finnish Cultural Foundation, Ida Montin Foundation, Aarne and Aili Turunen Foundation, Maud Kuistila Foundation, Aarne Koskelo Foundation, Paulo Foundation and Emil Aaltonen Foundation.


   Notes
 
Time for primary review 16 days


   References
Top
 Abstract
 1. Introduction
 2. Expression pattern and...
 3. Protein structure
 4. Cardiac target genes
 5. Activity and expression...
 6. Regulatory mechanisms
 7. Interactions with cofactors...
 8. Interactions with cofactors...
 9. Future perspectives
 10. Concluding remarks
 References
 

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