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Mechanical stimulus is critical to cardiovascular development during embryogenesis period.The mechanoreceptors of endocardial cells and cardiac myocytes may sense mechanical signals and initiate signal transduction that induce gene expression at a cellular level,and then translate molecular-level events into tissue-level deformations,thus guiding embryo development.This review summarizes the regulatory roles of mechanical signals in the early cardiac development including the formation of heart tube,looping,valve and septal morphogenesis,ventricular development and maturation.Further,we discuss the potential mechanical transduction mechanisms of platelet endothelial cell adhesion molecule 1-vascular endothelial-cadherin-vascular endothelial growth factor receptor 2 complex,primary cilia,ion channels,and other mechanical sensors that affect some cardiac malformations.
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Animals , Humans , Heart/embryology , Mechanotransduction, Cellular , Myocytes, Cardiac/physiology , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Epigenetic modification genes are defined as genes whose products modify the epigenome directly through DNA methylation, histone modification or chromatin remodeling.More and more studies have shown that mutations in epigenetic modification genes are an important etiology of rare diseases with abnormal cardiac development.And these diseases usually affect multiple organs including heart due to the change of epigenetic components.Moreover, children′s lives and health are often threatened by a lack of effective drugs and complex cardiovascular malformations.This article reviews advances in molecule genetics of Tatton-Brown-Rahman syndrome, Kabuki syndrome, Rubinstein-Taybi syndrome, CHARGE syndrome and Sifrim-Hitz-Weiss syndrome, and mainly elaborates the mechanism of cardiovascular malformations caused by mutations in corresponding epigenetic modification genes, providing more comprehensive reference for clinical diagnosis and management.
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BACKGROUND: NKX2-5 is an important transcriptional regulator during mammalian heart development. Studies from model animals such as rats, mice, and zebrafish have shown that the absence or abnormal function of NKX2-5 affects heart development, leading to pathological manifestations similar to human congenital heart disease. However, the regulatory role and specific mechanisms of NKX2-5 in cardiac development are still unclear. OBJECTIVE: To review the molecular structure, functional effects, and upstream and downstream regulatory molecules of NKX2-5. METHODS: The search terms “NKX2-5, congenital heart disease, CHD, heart development” were used for literature retrieval in the PubMed database (website https://www.ncbi.nlm.nih.gov/pubmed/). The deadline for publication was April 1, 2019. By downloading and reading the retrieved literature, articles irrelevant to NKX2-5 and with duplicate opinions and similar conclusions were excluded. Finally 97 eligible articles were taken for review. RESULTS AND CONCLUSION: (1) NKX2-5 plays a key role in the regulation of cardiac development. Abnormal functions or gene mutations of NKX2-5 can lead to abnormal cardiac development and dysfunction, which are closely related to the occurrence of human congenital heart disease. (2) The function of NKX2-5 depends on its functional domains. NKX2-5 enters the nucleus after transcription and translation, and activates or inhibits downstream regulatory molecules through binding with CO-factors or alone to specific DNA sequences, thereby regulating the proliferation, migration, differentiation and function of cardiac precursor cells and regulating the correct cardiac development process and the normal development and function of the cardiac conduction system. (3) The transcription, translation, nucleation process, transcription activation or inhibition of NKX2-5 is also regulated by various methods. These regulatory factors regulate NKX2-5 from the aspects of chromatin conformation, promoter and enhancer functions, RNA uncoiling, post-transcriptional modification, and nuclear localization.
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The NOTCH signaling pathway is an evolutionarily highly conserved signaling pathway that regulates various cellular physiological processes by conducting signals between adjacent cells,and is important for cell fate,cell development,differentiation,proliferation,apoptosis,adhesion,and epithelial-to-mesenchymal transition.The NOTCH pathway involves almost all aspects of cardiac development,including primitive heart patterning,and cardiac morphogenesis,which play a crucial role in cardiac development and postnatal cardiac homeostasis.It has been found that the conduction abnormality of the NOTCH pathway and the mutation of the NOTCH signal components are closely related to a series of congenital heart defects.Furthermore,NOTCH signaling can repair myocardial injury by promoting myocardial regeneration,protecting ischemic myocardium,inducing angiogenesis,and negatively regulating cardiac fibroblast-myofibroblast transformation.This article will focus on the role of NOTCH signaling pathways in mammalian hearts and its advances in congenital heart disease.
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Embryonic cardiogenesis requires precise expression of various genes.This process involves a complex model of gene regulation,in which any deviation will lead to the occurrence of heart defects.Expression of Tbx2 in different species is ultimately confined to the atrioventricular canal in the non-ventricular myocardium,suggesting that the temporal and spatial expression of Tbx2 gene during cardiac development is highly consistent and evolutionarily conserved.As a member of the T-box transcription factor family,Tbx2 plays an important role in the differentiation of outflow tract and atrioventricular canal,leading to a series of changes in the regulatory pathway by regulating the transcription levels of the downstream target genes.At present,more and more studies have indicated that aberrant expressions or regulations of Tbx2 result in cardiac malformations in different model animals.In clinical studies,microdeletions/duplications in the fragments involving TBX2 and genetic variants in the non-coding region of this gene have also been reported in human congenital heart defects.Thus,this article is to review the advances in the effect and possible mechanisms for Tbx2 gene in cardiac development,and to discuss the relationship between this gene and congenital heart defects.
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OBJECTIVE To explore the toxic effects of zinc oxide nanoparticls (ZnO-NPs) on cardiac development of zebrafish embryos and rat myocardial cell lines (H9c2),as well as potential molecular mechanisms.METHODS ZnO-NPs were characterized.Zebrafish embryos were exposed to different doses of ZnO-NPs (0,0.5,2.5,5.0 and 10.0 mg· L-1) for 24 to 96 h at 4 h post fertilization (4 hpf).The embryo mortality was observed.The expressions of notochord homeobox (noto),T-box 6 (tbx16),T,brachyury homolog a(ta),and tbx6 which were related to cardiac mesoderm were investigated using real-time PCR at 17 hpf.The heart rate and number of cardiomyocytes of embryos [[Tg (cmlc2:nucdsRed)] exposed to 0,2.5 and 5 mg· L-1 ZnO-NPs were detected at 72 hpf.Rat myocardial cell lines (H9c2) were treated with ZnO-NPs (0.1,0.5,1.0,5.0 and 10.0 mg· L-1) for 24 h.Cell viability was measured with Alamar Blue method.Mitochondrial ultrastructure was observed by transmission electron microscopy.Cellular ATP was detected using chemiluminescence,and oxygen consumption rate (OCR) was examined with Seahorse instrument.RESULTS The particle size of ZnO-NPs was (331 ±3)nm.The ZnO-NPs LC50 of zebrafish embryos at 48 hpf was 21.81 mg· L-1.The mRNA expressions of noto,ta and tbx6 were reduced after ZnO-NPs 2.5 mg· L-1 treatment at 17 hpf.The heart rate of 72 hpf zebrafish was 153 min-1 in the ZnO-NPs 5 mg· L-1 group,12.6％ lower than that in the cell vehicle group (P＜0.01),and the number of cardiomyocytes decreased by 15.5％ (P＜0.01) compared with the cell vehicle group.Reduced cell viability and mitochondrial vacuolation were observed in H9c2 after ZnO-NPs 0.5 mg· L-1 exposure.Compared with the cell vehicle group,the cell ATP decreased by 25.7％ (P＜0.05),and OCR decreased by 27.2％ (P＜0.01).CONCLUSION Low-dose ZnO-NPs exposure has effect on the cardiac development of zebrafish,mainly due to reduced heart rate and decreased number of cardiomyocytes.These changes may be related to the decreased expressions of cardiac development-related genes and the impairment of mitochondrial structure and function.
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Objective To explore the basic biological characteristics of lncRNA -uc.1 67,and its spatial dis-tribution,temporal expression pattern during the mouse embryonic development.Methods The UCSC genome browser of ENCODE was used to analyze preliminary bioinformatics of lncRNAs.Real -time (RT)-PCR was applied to detect the expression of uc.1 67 and neighboring genes in the embryonic mouse heart in different stages (P7.5,P1 1 .5,P1 4.5, P1 8.5).Dimethyl sulphoxide was used to induce P1 9 cell differentiation into the cardiomyocytes.RT -PCR was applied to detect the expression changes in uc.1 67 and neighboring genes on differential day 0,4,6,8 and 1 0.Results Full -length of human uc.167 was 201 bp,and human uc.167 was located in the genome 5q14.3 (chr5:88179623 -881 79824,GRCh37 /hg1 9).uc.1 67 mainly expressed in the ventricular muscle tissue.The expression of uc.1 67 was gradually decreased in the mouse embryonic heart development process(P7.5:1 .000 ±0.1 00,P1 1 .5:0.71 4 ±0.1 07, P1 4.5:0.393 ±0.043,P1 8.5:0.1 25 ±0.01 3),while the expression of its neighboring Mef2c gene was gradually in-creased(P7.5:1 .081 ±0.1 1 8,P1 1 .5:2.340 ±0.351 ,P1 4.5:3.958 ±0.542,P1 8.5:9.361 ±0.722),which showed an opposite trend.The expression of uc.1 67 during P1 9 cell differentiation into cardiomyocytes showed a an increase at first and then a decreasepattern,and the highest level expression of uc.1 67 was on differential day 4(d0:1 .071 ± 0.1 1 7,d4:4.71 4 ±0.501 ,d6:3.572 ±0.41 4,d8:2.550 ±0.31 4,d1 0:0.786 ±0.085).The expression of neigh-boring gene Mef2c was in an opposite trend(d0:1 .01 2 ±0.041 ,d4:0.353 ±0.037,d6:2.470 ±0.329,d8:6.706 ± 0.682,d1 0:7.765 ±0.705).Conclusions It is suggested that uc.1 67 may take part in the process of embryonic heart development and may play a role through negatively regulating its neighboring gene Mef2c.
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Objective To explore the effects of miR -30c over -expression on early cardiac development of zebrafish.Methods The single -cell -stage zebrafish embryos were micro -injected with 3 different concentrations of miR -30c mimics in order to model the miR -30c over -expressed animal.Besides,the effects of miR -30c overex-pression on cardiac development were investigated.The mortality rate and the heart rate were assessed.Beside,the gross morphology and heart morphology of the zebrafish were observed.Moreover,the molecular mechanisms underlying miR -30c function in zebrafish cardiac development was explored,and in -situ hybridization was performed.Results Compared with the wild -type embryos,the mortality rate of zebrafish was increased with the rising miR -30c concen-tration.Furthermore,when the miR -30c mimic concentration was up to 8 μmol/L,the mortality rate reached 80% at 96 h post -fertilization.Simultaneously,the heart rate,which was viewed as an important index to cardiac function,was decreased.Moreover,the pericardial edema was getting worse over time with increasing concentration of overexpression. Then,the cardiac specific gene expression on the zebrafish embryos by whole -mount in situ hybridization was ex-plored.The area of the cardiac chamber was extended and the heart tube looping was negatively affected.Besides,the expression of atrioventricular canal marker genes was absent in zebrafish embryos from miR -30c over -expression groups.Conclusion miR -30c can impact the early cardiac development of zebrafish.
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It was previously revealed that noncoding RNAs, especially microRNAs, control cardiac genes and regulate heart function.Recently, growing evidence from high-throughput genomic platforms has confirmed that long non-coding RNAs ( lncRNAs) serve as new and enigmatic regulators in cardiac development and homeostasis.Nevertheless, lit-tle is known about their characteristics compared to microRNAs.Here, we review the latest progress on lncRNAs in cardiac biology and diseases, summarizing detailed knowledge of their functions and novel cardiac-related gene regulatory mecha-nisms in epigenetic processes.Finally, we highlight that lncRNAs could be promising therapeutic targets and diagnostic bi-omarkers in cardiac pathophysiology.
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Understanding heart development at a molecular level is a prerequisite for uncovering the causes of congenital heart diseases .Such knowledge can also greatly benefit therapeutic approaches that try to enhance cardiac regeneration or that involve the differentiation of resident cardiac progenitor cells .Wnt proteins have been shown to play multiple roles dur-ing cardiac development .They are extracellular growth factors that activate different intracellular signaling branches .Here, we summarize our current understanding of how these factors affect different aspects of cardiogenesis , from early specifica-tion of cardiac progenitors to later developmental steps , such as remodeling processes .
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AIM:To study the effect of Hand2 (one of basic helix-loop-helix proteins’ transcription factors) expression on the development of the cardiac tissues in the fetal rats from gestational diabetes mellitus ( GDM) parents, and to investigate the potential pathogenesis of GDM-induced congenital cardiac defects in rats.METHODS: The adult Spra-gue-Dawley female rats were randomly divided into blank control group (n=24), GDM group (n=30), negative control group ( n=30) and insulin intervened group ( n=30) .The GDM model was established by intraperitoneal injection of 2%streptozotocin (STZ, 40 mg/kg body weight) to the pregnant rats on the successive day.The rats in insulin intervened group were injected with intermediate-acting insulin in order to keep the fasting blood glucose in the normal range.The rats in negative control group were injected with citric acid-sodium citrate buffer solution in the same position.Blood glucose and body weight were examined every day 72 h after STZ injection.On E12, E15 and E19, the rats were anesthetized and the embryonic cardiac tissues were collected after caesarean section.The histopathological changes of the cardiac tissues were observed under microscope with HE staining.The expression of Hand2 was analyzed by the method of immunohisto-chemistry.The expression of Hand2 in the cardiac tissues at mRNA and protein levels was determined by real-time fluores-cence quantitative PCR and Western blotting.RESULTS:During the development of embryonic heart, the protein expres-sion of Hand2 in the cardiac tissues was showed dynamic changes.Observed on E12, obviously increased on E15, and at the highest level on E19.Compared with the other 3 groups, the protein and mRNA expression of Hand2 in GDM group was decreased at the time points of E12 and E15.CONCLUSION:The morbidity of fetal cardiac malformation is significantly increased in GDM group, suggesting that Hand2 may be involved in the development of cardiac malformation in GDM.
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Atrial fibrillation (AF) is the most common chronic arrhythmia and is characterized by erratic atrial electrical activity with atrial rates of 400-600 beats per minute.AF in regards to symptoms and thromboembolic risk (including stroke).The symptoms of AF are related to the loss of atrial mechanical activity (atrial contraction) and rapid ventricular heart rates both of which can reduce cardiac output and lead to congestive heart failure. Thromboembolism frequently cause stroke in AF patients.It’s happened in Mongolia more than in other countries. That is why there is big need to improve knowledge of familiar, local, district and other professional doctors. The lecture was written using guidelines for the management of atrial fibrillation.
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BackgroundDandy described first, about intervertebral disc hernia (1929). Mixter W.J and Barr J.S (1934) investigated that correlation of sciatica and lumbar disc hernia. Discectomy is most confirming surgery among all spine surgery. Asymptomatic lumbar disc hernia revealed in 70% of adult, by MRI. Spine disorder is first cause of disability of workers below 45 yrs, in European countries. International research for predisposing, risk factors of intervertebral disc hernia is widely confirmed, but diagnostic and treatment aspects are not completed.Materials and MethodsWe did computer aided search using key words “disc degeneration, risk factor, discectomy, lumbar disc hernia, spinal instrumentation” in online library: MEDLINE, E pub, PUBMED, HINARI, Mongolmed, years 1970-2011, also domestic research works from Central library of HSUM, Mongolia. We included article, case-control study, systematic review, case study.ConclusionIncidence and disability caused by lumbar disc hernia, requiring surgical treatment is common problem in world. By anatomical region, lumbar disc hernia is the highest. Research work revealed that patients who took surgical treatment different by gender (male:female=2:1), geographical region (US 160/100000, Switzerland 62/100000). At last 20 yrs, dramatically changed theory about predisposing factor of disc hernia. It is changed from mechanical load to genetic role. Disc degeneration disease is basis of disc hernia. Nucleus pulposus, annulus fibrosus losing own structure, containing moleculs, and water under degeneration. The risk factors are frequent heavy lifting, frequent twisting and bending, vibration, sedentary work, driving and overweight. The golden standard surgery of herniated disc of cervical area is anterior cervical discectomy and fusion (ACDF). Posterior screw fixation of lumbar vertebrae is most frequently confirming surgery among the world.
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Cardiovascular malformations are the most common type of birth defect and result in significant mortality worldwide. The etiology for the majority of these anomalies remains unknown but genetic factors are being recognized as playing an increasingly important role. Advances in our molecular understanding of normal heart development have led to the identification of numerous genes necessary for cardiac morphogenesis. This work has aided the discovery of an increasing number of monogenic causes of human cardiovascular malformations. More recently, studies have identified single nucleotide polymorphisms and submicroscopic copy number abnormalities as having a role in the pathogenesis of congenital heart disease. This review discusses these discoveries and summarizes our increasing understanding of the genetic basis of congenital heart disease. Over the past couple of decades, there has been a greater understanding of the molecular pathways regulating cardiac development. The development of gene targeting technology has led to the generation of a multitude of mouse models with cardiac developmental defects. These studies have led to the identification of numerous transcriptional regulators, signaling molecules and structural genes that are critical for normal cardiac morphogenesis. In addition, multiple genes have been identified that are controlled by these highly conserved molecular pathways.These investigations into the molecular mechanisms of cardiac development have assisted in the identification of genetic etiologies of CHD and provide evidence that many genes may have etiologic roles in human CHD.
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Planar cell polarity pathway regulates cell polarity and polarized cell movements.Recent studies in mouse models have found mutations in several genes in this pathway and specifically in the Vangl2 gene,which results in abnormalities in cardiac development,suggesting Vangl2 and this pathway play an important role in heart development.This review mainly elucidates the mechanisms regulated by the Vangl2 gene and PCP pathway during outflow tract development and the formation of the coronary vasculature.
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MiRNA can regulate cell proliferation and differentiation,and promote the development of organisms.Phosphoinositide 3-kinase/protein kinase B(PI3K/AKT) signaling pathway plays an important role in cell proliferation and differentiation,and also in organ and organization development.Studies concerning miRNA and PI3K/AKT signaling pathways in cardiac development and their relationship might help explain the pathogenesis of cardiac malformations and related diseases.
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Integrins are heterodimeric receptors composed of á and â transmembrane subunits that mediate attachment of cells to the extracellular matrix and counter-ligands such as ICAM-1 on adjacent cells. â2 integrin (CD18) associates with four different á (CD11) subunits to form an integrin subfamily, which has been reported to be expressed exclusively on leukocytes. However, recent studies indicate that â2 integrin is also expressed by other types of cells. Since the gene for â2 integrin is located in the region of human chromosome 21 associated with congenital heart defects, we postulated that it may be expressed in the developing heart. Here, we show the results from several different techniques used to test this hypothesis. PCR analyses indicated that â2 integrin and the áL, áM, and áX subunits are expressed during heart development. Immunohistochemical studies in both embryonic mouse and chicken hearts, using antibodies directed against the N- or C-terminal of â2 integrin or against its á subunit partners, showed that â2 integrin, as well as the áL, áM, and áX subunits, are expressed by the endothelial and mesenchymal cells of the atrioventricular canal and in the epicardium and myocardium during cardiogenesis. In situ hybridization studies further confirmed the presence of â2 integrin in these various locations in the embryonic heart. These results indicate that the â2 integrin subfamily may have other activities in addition to leukocyte adhesion, such as modulating the migration and differentiation of cells during the morphogenesis of the cardiac valves and myocardial walls of the heart.
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Animals , Chick Embryo , Female , Mice , Pregnancy , /metabolism , Cell Differentiation/physiology , Cell Movement/physiology , Gene Expression Regulation, Developmental/physiology , Morphogenesis/physiology , /genetics , Embryo, Mammalian , Heart/embryology , Myocardium/metabolismABSTRACT
The Wnt/β-catenin signal transduction pathway is essential for regulating cell proliferation, movement, differentiation and embryo development. Researchers have found that Wnt pathway is an important regulation factor in the early stimulation of the cardiogenesis and contacts closely the several key events during cardiac morphogenesis. The article reviews the recent studies about the relation between cardiac development and Wnt pathway in early embryo.
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The Wnt/?-catenin signal transduction pathway is essential for regulating cell proliferation,movement,differentiation and embryo development. Researchers have found that Wnt pathway is an important regulation factor in the early stimulation of the cardiogenesis and contacts closely the several key events during cardiac morphogenesis. The article reviews the recent studies about the relation between cardiac development and Wnt pathway in early embryo.
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Objetivo: Comparar o crescimento volumétrico total do coraçäo (C), do miocárdio ventricular (MV) e dos coxins endocárdicos (CE) entre si e com o crescimento do embriäo. Coleçäo de embriöes humanos seccionados em série e corados (27 embriöes) no período pós-somítico. Os volumes de C, MV e CE foram determinados morfometricamente e correlacionados estatisticamente ao comprimento vertex-coccyx (V-C) dos embriöes pela equaçäo alométrica Y = a x**b. O crescimento cardíaco e de seus componentes MV e CE apresentou correlaçöes estatisticamente significativas (p<0,01), mas alometricamente negativas, em relaçäo ao crescimento de V-C. Isto indica que o coraçäo apresenta, mais intensamente modificaçöes na forma que no tamanho. Entretanto, em relaçäo ao coraçäo, MV é a estrutura que apresenta maior aumento relativo no segundo mês gestacional. Comparativamente, CE decresce nesse período e termina com menos de 3% do volume final do coraçäo. Os CE näo têm a importância anteriormente atribuída no desenvolvimento das valvas e dos septos cardíacos. Pelo contrário, alteraçöes no crescimento do MV devem interferir profundamente no desenvolvimento cardíaco
Purpose: To compare the volumetric growth of the whole heart (WH), ventricular myocardium (VM), and endocardial cushions (EC) among each other and in relation to the growth of the embryo. Patients and Methods: Collection of human embryos serially sectioned and stained (27 embryos) in post-somitic period. The volumes of WH, VM and EC were morphometrically determined and statistically correlated to the embryos crown-rump length (C-R) by using the allometric equation Y = a xb. Results: The cardiac growth, and the growth of the VM and EC, presented significant (p < 0.01) but allometically negative correlations in relation to C-R length. It indicates that cardiac changes in shape are more pronounced than in size. However, relative to the heart itself VM is the component that presents greater volumetric increase during the second month of gestation. EC decreases and end the embryonic period proper with less of 3% of the cardiac volume. Conclusion: Our quantitative results agree with more recent morphological studies which consider EC with small significance in valves and septa development, probably functioning more as a plastic component than in genesis of cardiac structures. On the contrary some lack in growth of the VM should disturb deeply cardiac development.