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At least 91 records · Page 5Linked to original sources
PubMed1999

Sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2) gene products are regulated post-transcriptionally during rat cardiac development.

OBJECTIVE: The Sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2) plays a major role in the contraction-relaxation cycle and is responsible for transporting calcium into the lumen of the sarcoplasmic reticulum. This study was performed to determine if the increase in SERCA2 messenger RNA (mRNA) abundance during the perinatal period is regulated transcriptionally. METHODS: Transcriptional activity was determined by nuclear run-on assays and mRNA and protein abundances were determined during late fetal and early neonatal cardiac development in rat. RESULTS: From nuclear run-on assays, SERCA2 gene transcription at 17/18 embryonic days (139 +/- 41 parts per million (ppm), n = 7) did not differ from that at 20 neonatal days (139 +/- 37 ppm, n = 6) after birth. No increase in transcriptional activity could be demonstrated during the time frame examined. In contrast, both alpha and beta myosin heavy chains showed significant changes in measured transcriptional activity. SERCA2 mRNA normalized to 18S RNA levels are very low in the fetus (9.8 +/- 1.9 to 13.4 +/- 4.9 arbitrary units (A.U.) from 17/18 to 19/20 embryonic days) and significantly increase from birth (15 +/- 3.8 A.U.) to reach a maximum at 20 days of age (29.1 +/- 9.5 to 48.3 +/- 7.0 in 15 to 20 neonatal days rats respectively). Similarly, SR Ca(2+)-ATPase protein levels are less abundant in the fetus (0.82 +/- 0.08 to 1.13 +/- 0.13 A.U./microgram total protein) and reach a maximum at 15-20 neonatal days (3.08 +/- 0.58 to 2.98 +/- 0.17). Ca2+ uptake in the fetal heart is about one sixth the level seen in the adult, reaches the highest observed value at 5 days after birth (6.05 +/- 0.77 pmole Ca2+ per microgram/min) and remains relatively constant over the next 15 days. The activity increases even though phospholamban protein increases in abundance. CONCLUSIONS: Since the transcriptional activity of this gene is unchanged whereas the mRNA, protein abundance and activity increase, we conclude that the abundance of SERCA2 gene products is regulated primarily through post-transcriptional mechanisms during the perinatal period.

Animals↗
PubMed1988

Dysplastic cardiac development presenting as cardiomyopathy.

Multiple manifestations of disordered or arrested cardiac muscle development are reported in a 14-year-old boy with clinical evidence of heart disease. These include persistent noncommunicating intramyocardial sinusoids, anomalous right ventricular muscle bands, muscular deficiency of ventricular septum, and papillary muscle underdevelopment. To our knowledge, this complex of findings has not been previously described.

Adolescent↗
PubMed2002

Optical coherence tomography: a new high-resolution imaging technology to study cardiac development in chick embryos.

BACKGROUND: Optical coherence tomography (OCT) is a depth-resolved, noninvasive, non-destructive imaging modality, the use of which has yet to be fully realized in developmental biology. METHODS AND RESULTS: We visualized embryonic chick hearts at looping stages using an OCT system with a 22 micro m axial and 27 micro m lateral resolution and an acquisition rate of 4000 A-scans per second. Normal chick embryos from stages 14 to 22 and sham-operated and cardiac neural crest-ablated embryos from stages 15 and 18 were scanned by OCT. Three-dimensional data sets were acquired and processed to create volumetric reconstructions and short video clips. The OCT-scanned embryos (2 in each group) were photographed after histological sectioning in comparable planes to those visualized by OCT. The optical and histological results showing cardiovascular microstructures such as myocardium, the cardiac jelly, and endocardium are presented. CONCLUSIONS: OCT is a powerful imaging modality which can provide new insight in assessing and understanding normal and abnormal cardiac development in a variety of animal models.

Animals↗
PubMed1994

Levels of the mitochondrial endonuclease during rat cardiac development implicate a role for the enzyme in repair of oxidative damage in mitochondrial DNA.

Mammalian heart mitochondria (MT) contain a potent Mg(2+)-dependent DNA endonuclease that becomes soluble once isolated mitochondria are disrupted using detergent. The level of this endonuclease was previously found to be markedly elevated in adult rat heart compared to other adult rat tissues. Among tissues, the level of the MT endonuclease does not appear to be correlated with the rate of MT DNA replication but rather with the rate of oxidative metabolism [Houmiel, K.L., Gerschenson, M. and Low, R.L., 1991. Biochimica Biophysica Acta 1079: 197-202]. In the present study, the level of the endonuclease has been quantitated both during rat cardiac development, from gestational day 18 through adulthood, and in cultured rat heart myoblasts. Surprisingly, the specific activity of the MT endonuclease in fetal and newborn mitochondria is high. The values are greater than 50% of that seen in the adult even though the mitochondria at this period of heart development are few and structurally disorganized. Remarkably, there is a burst of endonuclease activity at day 2 which accompanies a similar, transient elevation of respiratory complex I and IV activities. At later times, the endonuclease activity gradually increases until adulthood and correlates with steady increases in MT DNA and DNA polymerase-gamma. In cultured myoblasts, the level of the endonuclease increases about seven-fold as the growing cells reach confluency and differentiate into myotubes. These variations in the specific activity of the endonuclease, when considered along with other properties of the enzyme suggest that the endonuclease may serve a role in the removal of oxidative damage in MT DNA incurred from respiration.

Animals↗
PubMed1996

Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function.

The beta-adrenergic receptor kinase 1 (beta ARK1) is a member of the G protein-coupled receptor kinase (GRK) family that mediates the agonist-dependent phosphorylation and desensitization of G protein-coupled receptors. We have cloned and disrupted the beta ARK1 gene in mice by homologous recombination. No homozygote beta ARK1-/- embryos survive beyond gestational day 15.5. Prior to gestational day 15.5, beta ARK1-/- embryos display pronounced hypoplasia of the ventricular myocardium essentially identical to the "thin myocardium syndrome" observed upon gene inactivation of several transcription factors (RXR alpha, N-myc, TEF-1, WT-1). Lethality in beta ARK1-/- embryos is likely due to heart failure as they exhibit a > 70% decrease in cardiac ejection fraction determined by direct in utero intravital microscopy. These results along with the virtual absence of endogenous GRK activity in beta ARK1-/- embryos demonstrate that beta ARK1 appears to be the predominant GRK in early embryogenesis and that it plays a fundamental role in cardiac development.

Animals↗
PubMed1990

Ischemic nucleotide breakdown increases during cardiac development due to drop in adenosine anabolism/catabolism ratio.

Our earlier work on reperfusion showed that adult rat hearts released almost twice as much purine nucleosides and oxypurines as newborn hearts did [Am J Physiol 254 (1988) H1091]. A change in the ratio anabolism/catabolism of adenosine could be responsible for this effect. We therefore measured the activity of adenosine kinase, adenosine deaminase, nucleoside phosphorylase and xanthine oxidoreductase in homogenates of hearts and myocytes from neonatal and adult rats. In hearts the activity of adenosine deaminase and nucleoside phosphorylase (10-20 U/g protein) changed relatively little. However, adenosine kinase activity decreased from 1.3 to 0.6 U/g (P less than 0.025), and xanthine oxidoreductase activity increased from 0.02 to 0.85 U/g (P less than 0.005). Thus the ratio in activity of these rate-limiting enzymes for anabolism and catabolism dropped from 68 to 0.68 during cardiac development. In contrast, the ratio in myocytes remained unchanged (about 23). The large difference in adenosine anabolism/catabolism ratio, observed in heart homogenates, could explain why ATP breakdown due to hypoxia is lower in neonatal than in adult heart. Because this change is absent in myocytes, we speculate that mainly endothelial activities of adenosine kinase and xanthine oxidoreductase are responsible for this shift in purine metabolism during development.

Adenosine↗
PubMed2000

Left-right asymmetry and cardiac looping: implications for cardiac development and congenital heart disease.

Proper morphogenesis and positioning of internal organs requires delivery and interpretation of precise signals along the anterior-posterior, dorsal-ventral, and left-right axes. An elegant signaling cascade determines left- versus right-sided identity in visceral organs in a concordant fashion, resulting in a predictable left-right (LR) organ asymmetry in all vertebrates. The complex morphogenesis of the heart and its connections to the vasculature are particularly dependent upon coordinated LR signaling pathways. Disorganization of LR signals can result in myriad congenital heart defects that are a consequence of abnormal looping and remodeling of the primitive heart tube into a multi-chambered organ. A framework for understanding how LR asymmetric signals contribute to normal organogenesis has emerged and begins to explain the basis of many human diseases of LR asymmetry. Here we review the impact of LR signaling pathways on cardiac development and congenital heart disease.

Abnormalities, Multiple↗
PubMed2006

The role of Wnt signalling in cardiac development and tissue remodelling in the mature heart.

The heart is one of the first organs to function in the developing embryo. Vertebrate heart development can be subdivided into different phases, e.g. specification of myo- and endocardial progenitor cells during the establishment of heart-forming fields within the anterior lateral plate mesoderm, formation of the linear heart tube by merging of the paired heart-forming fields in front of the foregut, looping of the heart tube and transformation of the tubular embryonic heart into the four-chambered heart. The molecular mechanisms underlying these processes are phylogenetically remarkably conserved and involve the activation of specific transcriptional programs by different extracellular growth factors. In this review, we will focus on the functions of the Wnt family of growth factors in normal cardiac development and in tissue remodelling in the mature heart under pathological conditions.

Animals↗
PubMed2003

TACE is required for fetal murine cardiac development and modeling.

Tumor necrosis factor-alpha converting enzyme (TACE) is a membrane-anchored, Zn-dependent metalloprotease, which belongs to the ADAM (a disintegrin and metalloprotease) family. TACE functions as a membrane sheddase to release the ectodomain portions of many transmembrane proteins, including the precursors of TNFalpha, TGFalpha, several other cytokines, as well as the receptors for TNFalpha, and neuregulin (ErbB4). Mice with TACE(DeltaZn/DeltaZn) null mutation die at birth with phenotypic changes, including failure of eyelid fusion, hair and skin defects, and abnormalities of lung development. Abnormal fetal heart development was not previously described. Herein, we report that TACE(DeltaZn/DeltaZn) null mutant mice by late gestation exhibit markedly enlarged fetal hearts with increased myocardial trabeculation and reduced cell compaction, mimicking the pathological changes of noncompaction of ventricular myocardium. In addition, larger cardiomyocyte cell size and increased cell proliferation were observed in ventricles of TACE(DeltaZn/DeltaZn) knockout mouse hearts. At the molecular level, reduced expression of epidermal growth factor receptor, attenuated protein cleavage of ErbB4, and changes in MAPK activation were also detected in TACE(DeltaZn/DeltaZn) knockout heart tissues. The data suggest that TACE-mediated cell surface protein ectodomain shedding plays an essential and a novel regulatory role during cardiac development and modeling.

ADAM Proteins↗
PubMed1999

Evidence for a role of Smad6 in chick cardiac development.

Bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta (TGF-beta) superfamily, are obligatory growth factors for early embryogenesis and heart formation. SMAD proteins transduce signals of the TGF-beta superfamily. We isolated chicken Smad6 (cSmad6), a member of inhibitory SMADs, and found its expression to be remarkably restricted to the developing heart, eyes, and limbs. cSmad6 expression was detected in the cardiogenic region of stage 5 embryos and overlapped Nkx2-5 and bmp-2, -4, and -7 expression. Throughout development, cSmad6 was expressed strongly in the heart, primarily in the myocardium, endocardium, and endocardial cushion tissue. Myocardial expression of cSmad6 was stronger in the forming septum, where highly localized expression of bmp-2 and -4 was also observed. Ectopically applied BMP-2 protein induced the expression of cSmad6, a putative negative regulator of BMP-signaling pathway, in anterior medial mesoendoderm of stage 4-5 embryos. In addition, blocking of BMP signaling using Noggin downregulated cSmad6 in cardiogenic tissue. cSmad1, one of the positive mediators of BMP signaling, was also expressed in cardiogenic region, but was not BMP-2 inducible. Our data suggest that cSmad6 has a role in orchestrating BMP-mediated cardiac development. We propose the possible mechanism of action of cSmad6 as modulating BMP signal by keeping a balance between constitutively expressed pathway-specific cSmad1 and ligand-induced inhibitory cSmad6 in the developing heart.

Amino Acid Sequence↗
PubMed1995

Molecular cloning of a novel serine/threonine kinase, MRK, possibly involved in cardiac development.

We have isolated a novel member of putative serine/threonine kinase from a rat heart cDNA library using polymerase chain reaction methods. The novel kinase is transcribed as 2.6 kb mRNA encoding for a protein of 629 amino acids with the C-terminal non-catalytic portion. Amino acids analysis revealed that the N-terminal catalytic domain is 87% identical to the male-germ cell associated kinase (MAK), a cdc2-related serine/threonine kinase found to promote meiosis during spermatogenesis. Therefore, we designated this novel kinase as the MAK-related kinase (MRK). MRK protein, with a molecular weight of 66 kD, was shown to phosphorylate itself and the exogenous substrates, histone H1 and myelin basic protein. In addition, phosphoamino acid analysis confirmed the serine/threonine-specific protein kinase activity of MRK. Although MRK was ubiquitous in adult rat tissues, the expression of MRK protein in embryos was restricted primarily to embryonic myocardium during early organogenesis. This finding suggests that MRK may be a participant in cardiac development.

Amino Acid Sequence↗
PubMedDate not supplied

Transgenic animals as a tool for studying the effect of the c-myc proto-oncogene on cardiac development.

Transgenic animals provide a model system to elucidate the role of specific proteins in development. This model is now being used increasingly in the cardiovascular system to study cardiac growth and differentiation. During cardiac myocyte development a transition occurs from hyperplastic to hypertrophic growth. In the heart the switch from myocyte proliferation to terminal differentiation is synchronous with a decrease in c-myc mRNA abundance. To determine whether c-myc functions to regulate myocyte proliferation and/or differentiation, we examined the in vivo effect of increasing c-myc expression during fetal development and of preventing the decrease in c-myc mRNA expression that normally occurs during myocyte development. The model system used was a strain of transgenic mice exhibiting constitutive expression of c-myc mRNA in cardiac myocytes throughout development. Increased c-myc mRNA expression is associated with both atrial and ventricular enlargement in the transgenic mice. This increase in cardiac mass is secondary to myocyte hyperplasia, with the transgenic hearts containing greater than twice as many myocytes as nontransgenic hearts. The results of this study indicate that constitutive expression of c-myc mRNA in the heart during development results in enhanced hyperplastic growth, and suggest a regulatory role for the c-myc protooncogene in cardiac myogenesis.

Animals↗
PubMed2003

JUMONJI, a critical factor for cardiac development, functions as a transcriptional repressor.

JUMONJI (JMJ) is a nuclear factor that is critical for normal cardiovascular development, evidenced by the analysis of jmj homozygous mutant mice. However, the molecular function of JMJ remains to be elucidated. In the present study, we investigated whether JMJ is a transcriptional modulator. Reporter gene assays using the GAL4-DNA binding domain fused to JMJ and a reporter gene consisting of the GAL4 binding sites upstream of a luciferase reporter gene indicated that JMJ functions as a powerful transcriptional repressor. The DNA binding motif of JMJ was determined using CASTing experiments by incubating a random oligonucleotide library with the GST-JMJ fusion protein coupled to agarose beads. Among the selected binding oligonucleotides, the high affinity DNA binding sequences were identified by gel retardation assays. JMJ repressed expression of the reporter genes containing the high affinity JMJ binding sequences, indicating that JMJ is a DNA-binding transcriptional repressor. The domains for transcriptional repression, DNA binding, and nuclear localization signal were mapped by mutational analyses using reporter gene assays, gel retardation assays, and immunostaining experiments, respectively. The present data demonstrate for the first time that JMJ functions as a DNA-binding transcriptional repressor. Therefore, JMJ may play a critical role in transcription factor cascade to regulate expression of heart-specific genes and normal cardiac development.

Animals↗
PubMed2003

Effects of platelet-derived growth factor-AA and -BB on embryonic cardiac development.

Several studies have shown that disruption of the normal expression patterns of platelet-derived growth factor (PDGF) ligands and receptors during development results in gross cardiac defects and embryonic or neonatal death. However, little is known about the specific role that PDGF plays in the differentiation of cardiac myocytes. In experiments complementing studies that utilized naturally-occurring Patch mice lacking the PDGFr alpha, or knockout animals lacking a PDGF ligand or receptor, we used rat and mouse whole-embryo culture (WEC) techniques to increase the exposure of embryos to the PDGF-AA or -BB ligands. Following a 48-hr culture period, we analyzed heart growth and cardiac myocyte differentiation. Exposure of rat embryos to 50 ng/ml of PDGF-AA resulted in a 42% increase in total protein levels in the heart, but did not result in a significant increase in heart growth, as determined by measurements of the atrioventricular length and the left ventricular length and width. Exposure of embryos to 50 ng/ml of PDGF-BB resulted in a 77% increase in total protein levels and a significant (P < 0.05) 8-15% increase in the measured heart parameters. Although a comparison of control and PDGF-AA-treated embryos showed no increase in the overall size of the heart, confocal microscopy showed an increase in the size and number of myofibrillar bundles in the developing myocardium. In addition, transmission electron microscopy (TEM) revealed an increase in the presence of sarcomeres, indicating that myofibrils were more highly differentiated in these areas of the treated embryos. In PDGF-BB-treated embryos, the compact zone of the myocardium was thicker and, as shown by confocal microscopy and TEM, f-actin and well-developed sarcomeres were more prevalent, indicating that the myofibrils were more differentiated in the treated embryos than in the control embryos. These studies indicate that increased exposure of embryonic hearts to PDGF-AA or -BB increases the rate of myocardial development.

Animals↗
PubMed2006

The developing cardiac myocyte: maturation of excitability and excitation-contraction coupling.

The study of cardiac myocyte (CM) differentiation, development, and maturation is of interest for several compelling reasons. First, mechanisms of development are of fundamental biological interest. Second, congenital malformation of the heart may be related to CM dysfunction during embryonic/fetal development. Third, adult myocardium in a variety of diseased states re-expresses a fetal-like gene program. Fourth, the mature heart cannot readily regenerate itself. Thus, cell replacement therapy is an emerging treatment paradigm. Among the obstacles for the realization of cell replacement therapy is our incomplete understanding of the function during CM maturation. This is crucial in the potential use of embryonic stem (ES) cell-derived CMs as a cell source. Although much progress has been realized with mouse ES-CMs, our understanding of human counterparts is scant. Here we discuss key molecular underpinnings of excitability and excitation-contraction coupling in developing mouse heart. We focus on the Ca channel multimeric complex and Ca handling. We compare mouse embryonic physiology to that previously described in mouse ES-CMs and draw parallels and highlight distinctions to human ES-CMs. During mouse embryonic and fetal maturation, the L-type Ca channel current (I(Ca,L)) predominates, but embryonic/fetal I(Ca,L) has distinct properties from mature I(Ca,L). In addition T-type Ca current (I(Ca,T)) present in the fetus is not present in the adult. It is neither ethical nor practical to experiment with live human embryonic/fetal CMs for I(Ca) and Ca handling studies, but we can draw inferences from human heart cell function based on studies of human ES-CMs, using the parallels noted between mouse embryonic heart cells and mouse ES-CMs.

Animals↗
PubMedDate not supplied

Understanding cardiac development through the perspective of gene regulation and gene manipulation.

Cardiovascular malformations affect about 1% of newborns, yet much remains to be learned about the pathogenesis of these defects. Advances in understanding some of the molecular events involved in regulating cardiac morphogenesis are providing a new perspective with which to approach complex issues and questions related to congenital heart disease. More important, this new information provides not only unique opportunities for developing specific experimental models of congenital heart disease through direct genetic manipulation but also the basis for developing ways of therapeutically manipulating cardiac gene expression for some form of heart disease. This review presents recent advances in the understanding of the molecular aspects of cardiac development and how this information can be used to manipulate cardiac gene expression during development.

Animals↗
PubMed1998

Molecular insights into cardiac development.

Recent discoveries have led to a greater appreciation of the diverse mechanisms that underlie cardiac morphogenesis. Genetic strategies (primarily gene targeting approaches in mice) have significantly broadened research in cardiovascular developmental biology by illuminating new pathways involved in heart development and by allowing the genetic evaluation of pathways that have previously been implicated in these events. Advances have also been made using biochemical and cell- and tissue-based approaches. This review summarizes the author's interpretation of current trends in the effort to understand the molecular basis of cardiac-development, with an emphasis on insights obtained from genetic models.

Animals↗
PubMed1999

Fetal cardiac development and hemodynamics in the first trimester.

OBJECTIVE: To describe fetal cardiac and hemodynamic development in the first trimester of pregnancy. SUBJECTS AND METHODS: Forty-eight pregnancies were prospectively studied with transvaginal ultrasound and color Doppler. Fetal heart rate and size were documented together with the presence of inflow and outflow wave-forms and valve signals. RESULTS: Heart rate and size showed a positive correlation with gestational age. At 6 weeks of gestation, 20% of the cardiac cycle was occupied by the isovolumic contraction time (ICT); the isovolumic relaxation time (IRT) occupied 16% and remained unchanged, while the ICT progressively shortened and was not measurable after 12 weeks. The peak inflow velocities had changed from monophasic to biphasic by 10 weeks of gestation. At 7 weeks of gestation, semilunar valves were detected in 10% of examinations and the atrioventricular valves in 3%. The detection rate for both valves at 12 weeks was > or = 90%. In pregnancies that miscarried, the detection rate for both was < 25%. CONCLUSIONS: The Doppler signals that characterize the heart during the first trimester suggest effective heart compliance by 12 weeks. Normal valve development can be inferred from non-invasive Doppler recordings.

Female↗