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Developmental Biology Aug 2007Msx1 and Msx2 are highly conserved, Nk-related homeodomain transcription factors that are essential for a variety of tissue-tissue interactions during vertebrate...
Msx1 and Msx2 are highly conserved, Nk-related homeodomain transcription factors that are essential for a variety of tissue-tissue interactions during vertebrate organogenesis. Here we show that combined deficiencies of Msx1 and Msx2 cause conotruncal anomalies associated with malalignment of the cardiac outflow tract (OFT). Msx1 and Msx2 play dual roles in outflow tract morphogenesis by both protecting secondary heart field (SHF) precursors against apoptosis and inhibiting excessive proliferation of cardiac neural crest, endothelial and myocardial cells in the conotruncal cushions. During incorporation of SHF precursors into the OFT myocardium, ectopic apoptosis in the Msx1-/-; Msx2-/- mutant SHF is associated with reduced expression of Hand1 and Hand2, which from work on Hand1 and Hand2 mutants may be functionally important in the inhibition of apoptosis in Msx1/2 mutants. Later during aorticopulmonary septation, excessive proliferation in the OFT cushion mesenchyme and myocardium of Msx1-/-; Msx2-/- mutants is associated with premature down-regulation of p27(KIP1), an inhibitor of cyclin-dependent kinases. Diminished accretion of SHF precursors to the elongating OFT myocardium and excessive accumulation of mesenchymal cells in the conotruncal cushions may work together to perturb the rotation of the truncus arteriosus, leading to OFT malalignment defects including double-outlet right ventricle, overriding aorta and pulmonary stenosis.
Topics: Animals; Apoptosis; Body Patterning; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins; Cell Movement; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinase Inhibitor p27; DNA-Binding Proteins; Female; Fetal Heart; Gene Expression Regulation, Developmental; Genes, Homeobox; Heart Defects, Congenital; Homeodomain Proteins; MSX1 Transcription Factor; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Mutation; Neural Crest; Pregnancy; Signal Transduction; Transforming Growth Factor beta
PubMed: 17601530
DOI: 10.1016/j.ydbio.2007.05.037 -
PloS One Jul 2009Rapid growth of the embryonic heart occurs by addition of progenitor cells of the second heart field to the poles of the elongating heart tube. Failure or perturbation...
BACKGROUND
Rapid growth of the embryonic heart occurs by addition of progenitor cells of the second heart field to the poles of the elongating heart tube. Failure or perturbation of this process leads to congenital heart defects. In order to provide further insight into second heart field development we characterized the insertion site of a transgene expressed in the second heart field and outflow tract as the result of an integration site position effect.
RESULTS
Here we show that the integration site of the A17-Myf5-nlacZ-T55 transgene lies upstream of Hes1, encoding a basic helix-loop-helix containing transcriptional repressor required for the maintenance of diverse progenitor cell populations during embryonic development. Transgene expression in a subset of Hes1 expression sites, including the CNS, pharyngeal epithelia, pericardium, limb bud and lung endoderm suggests that Hes1 is the endogenous target of regulatory elements trapped by the transgene. Hes1 is expressed in pharyngeal endoderm and mesoderm including the second heart field. Analysis of Hes1 mutant hearts at embryonic day 15.5 reveals outflow tract alignment defects including ventricular septal defects and overriding aorta. At earlier developmental stages, Hes1 mutant embryos display defects in second heart field proliferation, a reduction in cardiac neural crest cells and failure to completely extend the outflow tract.
CONCLUSIONS
Hes1 is expressed in cardiac progenitor cells in the early embryo and is required for development of the arterial pole of the heart.
Topics: Animals; Base Sequence; Basic Helix-Loop-Helix Transcription Factors; Blotting, Western; Cell Proliferation; DNA Primers; Heart; Homeodomain Proteins; In Situ Hybridization; Mice; Mice, Transgenic; Morphogenesis; Myocardium; Transcription Factor HES-1; Transgenes
PubMed: 19609448
DOI: 10.1371/journal.pone.0006267 -
The Journal of Biological Chemistry Nov 2015About two-thirds of human congenital heart disease involves second heart field-derived structures. Histone-modifying enzymes, histone deacetylases (HDACs), regulate the...
About two-thirds of human congenital heart disease involves second heart field-derived structures. Histone-modifying enzymes, histone deacetylases (HDACs), regulate the epigenome; however, their functions within the second heart field remain elusive. Here we demonstrate that histone deacetylase 3 (HDAC3) orchestrates epigenetic silencing of Tgf-β1, a causative factor in congenital heart disease pathogenesis, in a deacetylase-independent manner to regulate development of second heart field-derived structures. In murine embryos lacking HDAC3 in the second heart field, increased TGF-β1 bioavailability is associated with ascending aortic dilatation, outflow tract malrotation, overriding aorta, double outlet right ventricle, aberrant semilunar valve development, bicuspid aortic valve, ventricular septal defects, and embryonic lethality. Activation of TGF-β signaling causes aberrant endothelial-to-mesenchymal transition and altered extracellular matrix homeostasis in HDAC3-null outflow tracts and semilunar valves, and pharmacological inhibition of TGF-β rescues these defects. HDAC3 recruits components of the PRC2 complex, methyltransferase EZH2, EED, and SUZ12, to the NCOR complex to enrich trimethylation of Lys-27 on histone H3 at the Tgf-β1 regulatory region and thereby maintains epigenetic silencing of Tgf-β1 specifically within the second heart field-derived mesenchyme. Wild-type HDAC3 or catalytically inactive HDAC3 expression rescues aberrant endothelial-to-mesenchymal transition and epigenetic silencing of Tgf-β1 in HDAC3-null outflow tracts and semilunar valves. These findings reveal that epigenetic dysregulation within the second heart field is a predisposing factor for congenital heart disease.
Topics: Animals; Body Patterning; Epigenesis, Genetic; Female; Fetal Heart; Heart Defects, Congenital; Heart Valves; Histone Deacetylases; Humans; Male; Mice; Mice, Knockout; Mice, Transgenic; Pregnancy; Signal Transduction; Transforming Growth Factor beta1
PubMed: 26420484
DOI: 10.1074/jbc.M115.684753 -
Atherosclerosis Mar 2013In addition to its effects on cholesterol levels, apoE3 has lipid-independent effects that contribute to cardiovascular protection; one of these effects is the ability...
OBJECTIVE
In addition to its effects on cholesterol levels, apoE3 has lipid-independent effects that contribute to cardiovascular protection; one of these effects is the ability to inhibit cell cycling in VSMCs. The goal of this study was to identify and characterize cell cycle-regulatory mechanisms responsible for the anti-mitogenic effect of apoE.
METHODS AND RESULTS
Primary VSMCs were stimulated with serum in the absence or presence of apoE3. apoE3 upregulated expression of the cdk inhibitor, p27(kip1), in primary VSMCs, and this effect required Cox2 and activation of PGI(2)-IP signaling. The microRNA family, miR221/222 has recently been identified as a post-translational regulator of p27, and apoE3 inhibited miR221/222 expression in a Cox2- and PGI(2)/IP-dependent manner. Moreover, reconstituted miR222 expression was sufficient to override the effects of apoE on p27 expression and S phase entry. The ability to repress expression of miR221/222 is shared by apoE3-containing HDL but is absent from apoA-1, LDL and apoE-depleted HDL. All three apoE isoforms regulate miR221/222, and the effect is independent of the C-terminal lipid-binding domain. miR221/222 levels are increased in the aortae of apoE3-null mice and reduced when apoE3 expression is reconstituted by adeno-associated virus infection. Thus, regulation of miR221/222 by apoE3 occurs in vivo as well as in vitro.
CONCLUSIONS
ApoE inhibits VSMC proliferation by regulating p27 through miR221/222. Control of cell cycle-regulatory microRNAs adds a new dimension to the spectrum of cardiovascular protective effects afforded by apoE and apoE-HDL.
Topics: Animals; Apolipoprotein E3; Cell Cycle Checkpoints; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p27; Cyclooxygenase 2; Male; Mice; MicroRNAs; Muscle, Smooth, Vascular
PubMed: 23294923
DOI: 10.1016/j.atherosclerosis.2012.12.003 -
Journal of the American Heart... Apr 2016Congenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar...
BACKGROUND
Congenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar valves account for >50% of these cases predominantly because of a bicuspid aortic valve, which has an estimated prevalence of 1% in the population. We previously reported that mutations in NOTCH1 were a cause of bicuspid aortic valve in nonsyndromic autosomal-dominant human pedigrees. Subsequently, we described a highly penetrant mouse model of aortic valve disease, consisting of a bicuspid aortic valve with thickened cusps and associated stenosis and regurgitation, in Notch1-haploinsufficient adult mice backcrossed into a Nos3-null background.
METHODS AND RESULTS
Here, we described the congenital cardiac abnormalities in Notch1(+/-);Nos3(-/-) embryos that led to ≈65% lethality by postnatal day 10. Although expected Mendelian ratios of Notch1(+/-);Nos3(-/-) embryos were found at embryonic day 18.5, histological examination revealed thickened, malformed semilunar valve leaflets accompanied by additional anomalies of the cardiac outflow tract including ventricular septal defects and overriding aorta. The aortic valve leaflets of Notch1(+/-);Nos3(-/-) embryos at embryonic day 15.5 were significantly thicker than controls, consistent with a defect in remodeling of the semilunar valve cushions. In addition, we generated mice haploinsufficient for Notch1 specifically in endothelial and endothelial-derived cells in a Nos3-null background and found that Notch1(fl/+);Tie2-Cre(+/-);Nos3(-/-) mice recapitulate the congenital cardiac phenotype of Notch1(+/-);Nos3(-/-) embryos.
CONCLUSIONS
Our data demonstrate the role of endothelial Notch1 in the proper development of the semilunar valves and cardiac outflow tract.
Topics: Animals; Aortic Valve; Bicuspid Aortic Valve Disease; DNA; DNA Mutational Analysis; Disease Models, Animal; Endothelial Cells; Female; Heart Valve Diseases; Heart Valves; Male; Mice; Mice, Mutant Strains; Mutation; Receptor, Notch1
PubMed: 27107132
DOI: 10.1161/JAHA.115.003075 -
Anesthesia, Essays and Researches 2018We present a 31-year-old primigravida with uncorrected pentalogy of Fallot, pregnant with monochorionic-diamniotic twins, undergoing elective lower segment cesarean...
We present a 31-year-old primigravida with uncorrected pentalogy of Fallot, pregnant with monochorionic-diamniotic twins, undergoing elective lower segment cesarean section at 36 weeks gestation. Preoperative workup included a transthoracic echocardiogram which revealed a large ventricular septal defect of 1.8 cm with bidirectional shunting, a moderate size atrial septal defect of 1.8 cm with predominant left-to-right shunting, an overriding aorta, moderate right ventricular hypertrophy, and severe pulmonary valve stenosis. Notably, the patient was acyanotic with normal effort tolerance. Preoperative preparation involved the input of cardiologists and obstetric and cardiothoracic anesthetists. Issues such as the use of extracorporeal membrane oxygenation and cardiopulmonary support in the event of cardiac failure were discussed. Autotransfusion postdelivery was also addressed, and plans made for therapeutic venesection should need to arise. Intraoperatively, the planned anesthetic technique was slow and titrated combined spinal-epidural. However, a general anesthetic technique with rapid sequence induction was used in view of extreme patient anxiety. Intravenous induction was performed with ketamine and etomidate, followed by paralysis with succinylcholine. Anesthesia was maintained with desflurane on a mixture of air and oxygen. Phenylephrine infusion was titrated according to the patient's blood pressure and systemic vascular resistance. The uterotonic of choice was duratocin given as a slow bolus, followed by a 4-h infusion of oxytocin. The patient was put in a head-up position to prevent venous air embolism and to decrease autotransfusion to central circulation. Postoperatively, she was extubated and sent to the Intensive Care Unit for continuous monitoring with FloTrac.
PubMed: 29628594
DOI: 10.4103/aer.AER_126_17 -
European Heart Journal. Case Reports Dec 2021Although the life expectancy of patients with tetralogy of Fallot (TOF) is comparable to that of the general population due to advancements in surgical intervention, if...
BACKGROUND
Although the life expectancy of patients with tetralogy of Fallot (TOF) is comparable to that of the general population due to advancements in surgical intervention, if untreated, patients with TOF may die during their childhood. However, it has been anecdotally reported that a small number of patients with unrepaired TOF survived into their senescence.
CASE SUMMARY
A 71-year-old man with a history of multiple heart failure admissions was referred to our institute after successful cardiopulmonary arrest resuscitation. Transthoracic echocardiography showed the overriding of the aorta on a large ventricular septal defect and right ventricular hypertrophy, along with severe pulmonary stenosis (PS), all of which indicated unrepaired TOF. Computed tomography revealed a patent Blalock-Taussig shunt, which was constructed at the age of 19 years. Coronary angiography revealed multivessel coronary stenoses. Although radical intracardiac repair was not performed due to his multiple comorbidities, his heart failure symptoms were significantly improved owing to proper medication titration. One year following discharge, the patient was well and enjoyed playing golf.
DISCUSSION
Specific anatomical, functional, and haemodynamic characteristics may be required for the long-term survival of patients with TOF. Pulmonary stenosis should be initially mild to guarantee pulmonary flow during childhood and adolescence, and gradual PS exacerbation should be paralleled with systemic-to-pulmonary collateral development or an extracardiac shunt. Moreover, reduced left ventricular compliance may act as a balancing factor against a right-to-left shunt. The presence of all of these special requirements may have contributed to the unusual survival for this patient.
PubMed: 35047736
DOI: 10.1093/ehjcr/ytab486 -
Journal of the American Heart... Sep 2017Wall shear stress (WSS) is a stimulus for vessel wall remodeling. Differences in ascending aorta (AAo) hemodynamics have been reported between bicuspid aortic valve...
BACKGROUND
Wall shear stress (WSS) is a stimulus for vessel wall remodeling. Differences in ascending aorta (AAo) hemodynamics have been reported between bicuspid aortic valve (BAV) and tricuspid aortic valve patients with aortic dilatation, but the confounding impact of aortic valve stenosis (AS) is unknown.
METHODS AND RESULTS
Five hundred seventy-one subjects underwent 4-dimensional flow magnetic resonance imaging in the thoracic aorta (210 right-left BAV cusp fusions, 60 right-noncoronary BAV cusp fusions, 245 tricuspid aortic valve patients with aortic dilatation, and 56 healthy controls). There were 166 of 515 (32%) patients with AS. WSS atlases were created to quantify group-specific WSS patterns in the AAo as a function of AS severity. In BAV patients without AS, the different cusp fusion phenotypes resulted in distinct differences in eccentric WSS elevation: right-left BAV patients exhibited increased WSS by 9% to 34% (<0.001) at the aortic root and along the entire outer curvature of the AAo whereas right-noncoronary BAV patients showed 30% WSS increase (<0.001) at the distal portion of the AAo. WSS in tricuspid aortic valve patients with aortic dilatation patients with no AS was significantly reduced by 21% to 33% (<0.01) in 4 of 6 AAo regions. In all patient groups, mild, moderate, and severe AS resulted in a marked increase in regional WSS (<0.001). Moderate-to-severe AS further increased WSS magnitude and variability in the AAo. Differences between valve phenotypes were no longer apparent.
CONCLUSIONS
AS significantly alters aortic hemodynamics and WSS independent of aortic valve phenotype and over-rides previously described flow patterns associated with BAV and tricuspid aortic valve with aortic dilatation. Severity of AS must be considered when investigating valve-mediated aortopathy.
Topics: Adult; Aged; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Valve; Aortic Valve Stenosis; Bicuspid Aortic Valve Disease; Blood Flow Velocity; Cross-Sectional Studies; Databases, Factual; Female; Heart Valve Diseases; Hemodynamics; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Phenotype; Predictive Value of Tests; Regional Blood Flow; Retrospective Studies; Severity of Illness Index; Stress, Mechanical
PubMed: 28903936
DOI: 10.1161/JAHA.117.005959 -
Medicina (Kaunas, Lithuania) Jul 2022The most common congenital cyanotic heart disease is described in the literature as the Tetralogy of Fallot. This abnormality is characterized by the presence of...
The most common congenital cyanotic heart disease is described in the literature as the Tetralogy of Fallot. This abnormality is characterized by the presence of ventricular septal defect (VSD), obstruction of the right ventricular (RV) outflow tract, right ventricular hypertrophy, and overriding aorta. In patients with pulmonary atresia with ventricular septal defect (PA/VSD), major aortopulmonary collateral arteries (MAPCA) are common; however, although some of them do not have PA/VSD, they do have other particular anatomical variants. The case we are presenting in this article is a rare mild symptomatic adult noncorrected TOF, with preserved RV function, right aortic arch, and MAPCAs ("classic" thoracic MAPCAs but also abdominal MAPCAs). The anatomy of a complex congenital defect is well illustrated by cardiac magnetic resonance (CMR) and computer tomography angiography (CTA), and these imaging techniques are mostly used to understand the relative clinical "silence" TOF. Imaging scans thus play a key role in the evaluation of these patients, being very important to know the indications and limitations of each method, but also to learn to combine them with each other depending on the clinical picture of the patient's presentation. Additionally, the close collaboration between clinicians and imagers is essential for a correct, complete and detailed preoperative evaluation, being subsequently essential for cardiovascular surgeons, the whole team thus deciding the best therapeutic management.
Topics: Adult; Aorta, Thoracic; Collateral Circulation; Humans; Infant; Pulmonary Artery; Retrospective Studies; Survivors; Tetralogy of Fallot
PubMed: 36013478
DOI: 10.3390/medicina58081011 -
American Journal of Physiology. Heart... Feb 2007On the basis of our previous studies on RhoA signaling in smooth muscle cells (SMC), we hypothesized that RhoA-mediated nuclear translocalization of the... (Comparative Study)
Comparative Study
On the basis of our previous studies on RhoA signaling in smooth muscle cells (SMC), we hypothesized that RhoA-mediated nuclear translocalization of the myocardin-related transcription factors (MRTFs) was important for regulating SMC phenotype. MRTF-A protein and MRTF-B message were detected in aortic SMC and in many adult mouse organs that contain a large SMC component. Both MRTFs upregulated SMC-specific promoter activity as well as endogenous SM22alpha expression in multipotential 10T1/2 cells, although to a lesser extent than myocardin. We used enhanced green fluorescent protein (EGFP) fusion proteins to demonstrate that the myocardin factors have dramatically different localization patterns and that the stimulation of SMC-specific transcription by certain RhoA-dependent agonists was likely mediated by increased nuclear translocation of the MRTFs. Importantly, a dominant-negative form of MRTF-A (DeltaB1/B2) that traps endogenous MRTFs in the cytoplasm inhibited the SM alpha-actin, SM22alpha, and SM myosin heavy chain promoters in SMC and attenuated the effects of sphingosine 1-phosphate and transforming growth factor (TGF)-beta on SMC-specific transcription. Our data confirmed the importance of the NH(2)-terminal RPEL domains for regulating MRTF localization, but our analysis of MRTF-A/myocardin chimeras and myocardin RPEL2 mutations indicated that the myocardin B1/B2 region can override this signal. Gel shift assays demonstrated that myocardin factor activity correlated well with ternary complex formation at the SM alpha-actin CArGs and that MRTF-serum response factor interactions were partially dependent on CArG sequence. Taken together, our results indicate that the MRTFs regulate SMC-specific gene expression in at least some SMC subtypes and that regulation of MRTF nuclear localization may be important for the effects of selected agonists on SMC phenotype.
Topics: Active Transport, Cell Nucleus; Animals; Aorta, Thoracic; Cell Differentiation; Cell Nucleus; Cells, Cultured; Lysophospholipids; Microfilament Proteins; Muscle Proteins; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Nuclear Proteins; Phenotype; Platelet-Derived Growth Factor; Promoter Regions, Genetic; RNA, Messenger; Rats; Serum Response Factor; Sphingosine; Time Factors; Trans-Activators; Transcription, Genetic; Transfection; Transforming Growth Factor beta; rhoA GTP-Binding Protein
PubMed: 16997888
DOI: 10.1152/ajpheart.00864.2006