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PubMed1997

A novel cardiac-restricted target for doxorubicin. CARP, a nuclear modulator of gene expression in cardiac progenitor cells and cardiomyocytes.

Doxorubicin (Dox), a cardiotoxic antineoplastic drug, disrupts the cardiac-specific program of gene expression (Kurabayashi, M., Dutta, S., Jeyaseelan, R., and Kedes, L. (1995) Mol. Cell. Biol. 15, 6386-6397; Jeyaseelan, R., Poizat, C., Wu, H. Y., and Kedes, L. (1997) J. Biol. Chem. 272, 5828-5832). To determine whether this drug might interfere with the function of cardiac-specific regulatory pathways, we used a differential display strategy to clone from neonatal rat cardiomyocyte candidate mRNAs that were rapidly sensitive to Dox. We report here the identification of a constitutively expressed, cardiac-restricted, nuclear protein whose mRNA level is exquisitely sensitive to Dox. Hence we have named this protein cardiac adriamycin-responsive protein (CARP). CARP mRNA is present at the earliest stages of cardiac morphogenesis. It was detected by in situ hybridization within the cardiogenic plate of 7. 5-day post coitum (p.c.) embryos, and in 8.5-day p.c. embryos CARP transcripts are present in uniformly high levels in the myocardium. Throughout cardiac development, CARP expression is specific for the myocardium; endocardial cushions and valves exhibit only background levels of signal. Transcript levels persist but gradually decrease in neonatal, 2-week-old, and adult hearts. There were no stages when CARP mRNA could not be detected. The pattern and timing of CARP mRNA expression, including transient expression in the tongue at 14.5 days p.c., coincides with that of Nkx2.5/Csx (a putative homolog of tinman, the Drosophila melanogaster gene responsible for cardiac development). The cloned full-length 1749 nucleotide CARP cDNA encodes a 319-amino acid 40-kDa polypeptide containing five tandem ankyrin repeats. CARP appears to be the rat homolog of a previously reported human single-copy gene (C-193; Chu, W., Burns, D. K., Swerlick, R. A., and Presky, D. H. (1995) J. Biol. Chem. 270, 10236-10245), whose mRNA is inducible by cytokines only in human endothelial cells. CARP appears to function as a negative regulator of cardiac-specific gene expression. Overexpression of CARP in cardiomyocytes suppresses cardiac troponin C and atrial natriuretic factor transcription. Cotransfection experiments in HeLa cells indicate that CARP inhibits Nkx2.5 transactivation of atrial natriuretic factor promoter. When fused to a GAL4 DNA-binding domain, CARP has transcriptional inhibitory properties in noncardiac cells. CARP thus represents the first example of a cardiac-restricted transcriptional regulatory protein that is sensitive to Dox.

Amino Acid Sequence↗
PubMed1988

A molecular view of cardiogenesis.

Cardiac development involves a complex integration of subcellular processes into multicellular and, finally, whole organ effects. Until recently it has been difficult to investigate the genetic control of this organ level differentiation of the heart. The proliferation of molecular biology methodologies has provided mechanisms to directly investigate the control of these processes. This article focuses on molecular lines of research on two key areas in cardiac development: the regulation of expression of sarcomeric contractile and regulatory proteins, and atrial natriuretic factor. Molecular approaches are described which have allowed investigators to begin to determine the tissue and stage-specific expression of genes, to locate those genes in the genome, determine their sequences, and to directly investigate the mechanisms controlling their expression.

Animals↗
PubMed1985

Atrial myxoma as a complication of tocolytic therapy. A case report.

A 27-year-old woman who presented with premature labor was given ritodrine for tocolysis. During the administration of the beta-sympathomimetics she developed cardiac changes, including subendocardial ischemia on EKG and an intermittent early diastolic sound. Echocardiography revealed a large left atrial myxoma. It was removed during pregnancy, and the patient tolerated the procedure well. The mechanism of the ischemia was believed to result from the space-occupying mass of the myxoma, preventing adequate atrial filling and subsequent congestive failure. It is recommended that patients who develop cardiac symptoms during tocolysis with beta-sympathomimetics undergo further investigation to rule out under-lying pathology.

Adult↗
PubMedDate not supplied

Congenital heart defects in siblings with partial aneuploidy of chromosome 2p.

Cytogenetic anomalies are found in 13% of children with congenital heart disease, providing positional information that may aid in identifying genes governing cardiac development. We report two children born to a clinically normal female with a balanced chromosomal rearrangement, resulting from insertion of 2p24.2-p25.1 into chromosome 1. Each of her offspring had complex congenital heart disease, including left ventricular hypoplasia, and inherited a different copy number of the 2p segment. These findings suggest that proper dosage of a gene or genes in this region is important in normal cardiac development.

Aneuploidy↗
PubMed2006

[Investigation on spontaneous electrical activity of murine embryonic heart using microelectrode arrays].

In our studies, we have applied a novel tool, microelectrode arrays (MEA), to investigate the electrophysiological properties of murine embryonic hearts in vitro. The electrical signals were recorded from the areas of the heart adhering to the 60 MEA electrodes, being called field potentials (FPs). As an extracelluar recording, the waveform of the FP appeared similar to a reversed action potential obtained from single cell by whole cell current clamp and the FP duration was comparable with the action potential duration. To study propagation of spontaneous electrical activity, we have compared the occurrence time of FPs recorded from different electrodes. It is shown that there was already an apparent A-V delay [(50.21+/-9.7) ms] at day 9.5 post coitum (E9.5) when heart was still tubular-like and atrium and ventricle were not separated anatomically, while occurence of FP at different electrodes of ventricular area were almost synchronous. Further, we looked into the modulation of spontaneous electrical activity during cardiac development: at E9.5 of embryonic development, 1 mumol/L of isoproterenol (Iso) increased beating frequency by (34.04+/-7.31)%, shortened the A-V delay by (20.00+/-6.44) % and prolonged FP duration. In contrast, 1 mumol/L of carbachol (CCh) slowed down beating frequency by (42.32+/-5.36) %, A-V conduction by (26.00+/-4.81) % and shortened FP duration; however at late stage (E16.5), the regulatory effect of Iso and CCh was strengthened. Therefore we conclude that cardiac conduction system is already established at E9.5 when the four-chambered heart is not formed yet and the regulation of spontaneous activity by sympathetic and para-sympathetic system is gradually matured during cardiac development.

Action Potentials↗
PubMed1990

Regional differences in in vivo myocardial protein synthesis in the neonatal rabbit heart.

Left ventricular free wall (LV) myofibrillar proteins accumulate at a rate approximately 2.5 times faster than the rate of right ventricular free wall (RV) proteins during postnatal cardiac development of the rabbit heart. In this study, the contribution of regional differences in in vivo protein synthesis to the differential rates of growth of the RV and LV myocardium was assessed in 4-d, 3-wk, and 9-wk old rabbits. In vivo total protein fractional synthetic rates were measured by a modification of the flooding infusion method, with calculations based upon the rate of equilibration of plasma leucine and cardiac leucyl-tRNA specific radioactivities following intravenous administration of a large dose of labeled amino acid. This method was also applied to the analysis of the fractional synthetic rate of a contractile protein subunit (myosin heavy chain) in the RV and LV of 4-d and 9-wk old rabbits. Accelerated growth of the LV during the first week of postnatal cardiac development was associated with increased total protein fractional synthetic rates (35.3 +/- 3.6 vs. 45.5 +/- 4.7%/day for RV and LV total protein of 4-d old rabbits, respectively). In addition, RV and LV fractional synthetic rates for myosin heavy chain in the same 4-d old rabbits were considerably greater than those values observed for total protein (84.0 +/- 13.1 and 98.4 +/- 16.9%/day for RV and LV myosin heavy chain, respectively. However, the fractional synthetic rates of both total protein and myosin heavy chain in both the RV and LV rapidly declined during the transition from fetal to adult hemodynamics. Thus, regional and developmental differences in myocyte-specific protein synthesis both contribute to the extensive restructuring of ventricular muscle during this period of extremely rapid growth. These differences may be in response to regional and developmental changes in hemodynamic load.

Aging↗
PubMed2006

Re-employment of developmental transcription factors in adult heart disease.

A finite number of transcription factors constitute a combinatorial code that orchestrates cardiac development and the specification and differentiation of myocytes. Many, if not all of these same transcription factors are re-employed in the adult heart in response to disease stimuli that promote hypertrophic enlargement and/or dilated cardiomyopathy, as part of the so-called "fetal gene program". This review will discuss the transcription factors that regulate the hypertrophic growth response of the adult heart, with a special emphasis on those regulators that participate in cardiac development.

Adult↗
PubMed2005

Calreticulin signals upstream of calcineurin and MEF2C in a critical Ca(2+)-dependent signaling cascade.

We uncovered a new pathway of interplay between calreticulin and myocyte-enhancer factor (MEF) 2C, a cardiac-specific transcription factor. We establish that calreticulin works upstream of calcineurin and MEF2C in a Ca(2+)-dependent signal transduction cascade that links the endoplasmic reticulum and the nucleus during cardiac development. In the absence of calreticulin, translocation of MEF2C to the nucleus is compromised. This defect is reversed by calreticulin itself or by a constitutively active form of calcineurin. Furthermore, we show that expression of the calreticulin gene itself is regulated by MEF2C in vitro and in vivo and that, in turn, increased expression of calreticulin affects MEF2C transcriptional activity. The present findings provide a clear molecular explanation for the embryonic lethality observed in calreticulin-deficient mice and emphasize the importance of calreticulin in the early stages of cardiac development. Our study illustrates the existence of a positive feedback mechanism that ensures an adequate supply of releasable Ca(2+) is maintained within the cell for activation of calcineurin and, subsequently, for proper functioning of MEF2C.

Animals↗
PubMed2005

The role of PPARgamma-dependent pathway in the development of cardiac hypertrophy.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. PPARs have three isoforms, alpha, beta (or delta) and gamma. It has been conceived that PPARgamma is expressed predominantly in adipose tissue and promotes adipocyte differentiation and glucose homeostasis. Recently, synthetic antidiabetic thiazolidinediones and natural prostaglandin D2 (PGD2) metabolite, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), have been identified as ligands for PPARgamma. Following demonstration that PPARgamma is present in a variety of cell types, further study of PPARgamma has been conducted. Although activation of PPARgamma appears to have beneficial effects on atherosclerosis and heart failure, it is still largely uncertain whether PPARgamma ligands prevent the development of cardiovascular diseases. Recent evidence suggests that some benefit from the antidiabetic agents known as thiazolidinediones may occur through PPARgamma-independent mechanisms. In this review, we report on the latest developments concerning the study of PPARs and summarize the roles of the PPARgamma-dependent pathway in cardiovascular diseases.

Cardiomegaly↗
PubMed1999

Development of cardiac rhythms in altricial avian embryos.

Mean heart rate (MHR) was determined during incubation and in hatchlings of 14 altricial avian species to investigate (1) if there is a common developmental pattern of heart rate in altricial embryos and (2) if heart rate changes during incubation are correlated with changes in embryonic growth rate. On the basis of normalized incubation MHR increased approximately linearly in 12 of 14 species from as early as 30-40% of incubation to that of pipped embryos. The MHR of hatchlings was equal to or higher than that of pipped embryos in seven species. Passerine embryos and hatchlings maintained higher MHR in comparison to parrots of similar egg mass, which may reflect phylogenetic differences in development. Embryonic MHR increased at a higher rate while embryonic growth rates were highest during the first 40% of incubation in tit, budgerigar and crow embryos than during subsequent development when relative growth rates decreased. MHR became independent of yolk-free wet mass at a smaller fraction of hatchling mass in budgerigar and crow than in the tit, suggesting that MHR is more likely to increase continuously after 40% of incubation in small altricial species than larger species.

Animals↗
PubMed2003

The role of PPARgamma-dependent pathway in the development of cardiac hypertrophy.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. PPARs have three isoforms, alpha, beta (or delta) and gamma. It has been conceived that PPARgamma is expressed predominantly in adipose tissue and promotes adipocyte differentiation and glucose homeostasis. Recently, synthetic antidiabetic thiazolidinediones and natural prostaglandin D(2) (PGD(2)) metabolite, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), have been identified as ligands for PPARgamma. Following demonstration that PPARgamma is present in a variety of cell types, further study of PPARgamma has been conducted. Although activation of PPARgamma appears to have beneficial effects on atherosclerosis and heart failure, it is still largely uncertain whether PPARgamma ligands prevent the development of cardiovascular diseases. Recent evidence suggests that some benefit from the antidiabetic agents known as thiazolidinediones may occur through PPARgamma-independent mechanisms. In this review, we report on the latest developments concerning the study of PPARs and summarize the roles of the PPARgamma-dependent pathway in cardiovascular diseases.

Animals↗
PubMed1999

Prenatal detection and mapping of a distal 8p deletion associated with congenital heart disease.

We report the prenatal diagnosis, at 18 weeks' gestational age of a del(8)(p23.1-->pter) in a fetus with an atrio-ventricular canal, persistent left superior vena cava and hypoplastic right ventricle detected by sonographic imaging. We further refine the breakpoints associated with this defect using fluorescent in situ hybridization analysis (FISH). Our findings correlate with recent reports of the localization and importance of GATA4 (a zinc finger transcription factor) in cardiac development. Though microcephaly, mental retardation and typical behavioural features are well described in various deletions in 8p, the absence of notable microcephaly in this case raises the possibility for a separate genetic aetiology for some of these features. Indeed, primary autosomal recessive microcephaly (MCPH1) was recently mapped to a nearby region and may be the cause for this frequent observation in some cases of 8p deletions. These observations illustrate the role of FISH in prenatal diagnosis and refinement of chromosomal breakpoints. In addition, mappings of loci significant for cardiac development are presented. Our findings suggest that some features of the 8p deletion syndrome may ultimately be uncoupled from one another, and underscore the need for further study of this region of chromosome 8, in order to achieve adequate information for genetic counselling.

Adult↗
PubMed1994

Changes in the microvascular network during cardiac growth, development, and aging.

Quantitative changes in the terminal vascular bed of the mammalian heart were assessed during postnatal development and aging. The most striking feature is a considerable formation of new capillaries in the early postnatal period, accompanied by a moderate formation of new arterioles. On the other hand, coronary arterioles seem to disappear at a higher rate than capillaries in the senescent heart. We proposed a three-dimensional structural model of tissue capillary supply, defined as capillary domain area times capillary segment length. This so called capillary supply unit increases as a function of age and body growth. It is very similar in size and shape (length to width ratio) to cardiac myocytes.

Adult↗
PubMed1995

bFGF promotes functional expression of transient outward currents in cultured neonatal rat ventricular cells.

To investigate the effect of basic fibroblast growth factor (bFGF) on ion channel expressions in developing cardiac cells, a short-term primary culture of ventricular myocytes isolated from day-old newborn rats was established. Functional expressions of the transient outward currents (Ito) were measured by whole-cell voltage-clamp method. Addition of 40 ng/ml bFGF to the serum-free culture medium for 72 hours increased the Ito density without influences on membrane capacitance of the myocytes, an estimate of cell size. bFGF also promoted expressions of the steady-state outward currents. Methyl 2,5-dihydroxycinnamate (3 microM), a tyrosine kinase inhibitor, showed preferential inhibition of the bFGF-stimulated increase in Ito density. These results suggest that bFGF may play a role in regulating ion channel expressions of developing cardiac cells via activation of bFGF receptor tyrosine kinase activity.

Animals↗
PubMed2006

T cell costimulation in the development of cardiac allograft vasculopathy: potential targets for therapeutic interventions.

Cardiac allograft vasculopathy (CAV) is a form of coronary arterial stenosis and a leading cause of death in patients who survive beyond the first year after heart transplantation. Histopathologically, this lesion is concentric diffuse intimal hyperplasia of the arterial wall that is accompanied by extensive infiltration of inflammatory cells, including T cells. Many studies have explored the potential risk factors related to this arterial lesion and its pathogenesis. Continuous minor endothelial cell damage evokes inflammatory processes including T cell activation. Costimulatory molecules play crucial roles in this T cell activation. Many costimulatory pathways have been described, and some are involved in the pathogenesis of CAV, atherogenesis, and subsequent plaque formation. In this review, we summarize the present knowledge of the role of these pathways in CAV development and the possibility of manipulating these pathways as a means to treat heart allograft vascular disease and atherosclerosis.

Coronary Stenosis↗
PubMed2001

Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation.

The cardiac homeobox protein Nkx2-5 is essential in cardiac development, and mutations in Csx (which encodes Nkx2-5) cause various congenital heart diseases. Using the yeast two-hybrid system with Nkx2-5 as the 'bait', we isolated the T-box-containing transcription factor Tbx5; mutations in TBX5 cause heart and limb malformations in Holt-Oram syndrome (HOS). Co-transfection of Nkx2-5 and Tbx5 into COS-7 cells showed that they also associate with each other in mammalian cells. Glutathione S-transferase (GST) 'pull-down' assays indicated that the N-terminal domain and N-terminal part of the T-box of Tbx5 and the homeodomain of Nkx2-5 were necessary for their interaction. Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation. Deletion analysis showed that both the N-terminal domain and T-box of Tbx5 were important for this transactivation. A G80R mutation of Tbx5, which causes substantial cardiac defects with minor skeletal abnormalities in HOS, did not activate Nppa or show synergistic activation, whereas R237Q, which causes upper-limb malformations without cardiac abnormalities, activated the Nppa promoter to a similar extent to that of wildtype Tbx5. P19CL6 cell lines overexpressing wildtype Tbx5 started to beat earlier and expressed cardiac-specific genes more abundantly than did parental P19CL6 cells, whereas cell lines expressing the G80R mutant did not differentiate into beating cardiomyocytes. These results indicate that two different types of cardiac transcription factors synergistically induce cardiac development.

Atrial Natriuretic Factor↗
PubMed2006

Heart-targeted overexpression of Nip3a in zebrafish embryos causes abnormal heart development and cardiac dysfunction.

We transiently expressed a proapoptotic protein, Nip3a, by a heart-specific BMP4 promoter in zebrafish embryos and generated two variants of embryos with abnormal heart phenotypes (A and B). Embryos with phenotype A heart defects showed hypoplastic or elongated ventricles, elongated or enlarged atriums with no normal cardiac looping resulting a significant longer SV-BA distance, and bradycardia at 48 h post-fertilization (hpf). Embryos with phenotype B heart defects showed an enlarged fluid-filled pericardium, severe hypoplasia, non-contracting ventricles, and elongated or enlarged slowly beating atriums with no normal looping. Histological sections further revealed the absence of a proper atrioventricular boundary and no endocardial cells lining this region in both 48- and 72-hpf Nip3a-overexpressing embryos, implicating defective endocardial cushion formation. These phenotypes are reminiscent of atrioventricular canal defects in humans. In addition, induced apoptotic myocardium cells were clustered in the presumptive atrioventricular boundary as well as in the adjacent ventricle and atrium of 48- and 72-hpf Nip3a-overexpressing embryos. Nip3a expression was readily detected in 80% epiboly BMP4-Nip3a-injected embryos, and defects in heart development were observed in both the linear heart tube and subsequent chamber formation stages. These results showed that myocyte apoptosis is a universal pathogenic factor for congenital heart failure using zebrafish as a model organism.

Animals↗
PubMed2006

The roles of Groucho/Tle in left-right asymmetry and Kupffer's vesicle organogenesis.

The heart is the first organ to form and function in the vertebrate embryo. Furthermore, differences between the left and right sides of the embryo become first detectable during cardiac development. We observed strong cardiac laterality phenotypes in medaka embryos by manipulating Groucho protein activity. The phenotypes produced by misexpressing Tle4 and the dominant-negative Aes reveal a general effect of these corepressor proteins on left-right (LR) development. With the help of an inducible expression system, we were able to define temporally different phases for these effects. In an early phase during gastrulation, Groucho proteins regulate Brachyury expression in the dorsal forerunner cells, which later gives rise to the Kupffer's vesicle (KV). The interference of endogenous Groucho proteins by misexpression of Aes leads to KVs of reduced size, whereas overexpression of Tle4 results in enlarged KVs. The expression level of the cilia marker Lrd was also affected both positively and negatively from these treatments. In the late phase during somitogenesis, Groucho proteins regulate the asymmetric activities of Nodal and Lefty genes. Altering canonical Wnt signaling produced similar results in late embryos, however, this did not affect KV morphogenesis or Lrd expression in early embryos. Therefore, changes in Kupffer's vesicle morphogenesis and the laterality of visceral organs following alterations in Groucho corepressor levels demonstrate two distinct phases in which Groucho proteins help establish LR asymmetry in medaka fish.

Amino Acid Sequence↗