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Novel Point Mutations in 3'-Untranslated Region of gata4 Gene Are Associated with Sporadic Non-syndromic Atrial and Ventricular Septal Defects

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Current Medical Science 2022年第1期42卷 129-143页

作者： Mehri KHATAMI Sajedeh GHORBANI Mojgan Rezaii ADRIANI Sahar BAHALOO Mehri Azami NAEINI Mohammad Mehdi HEIDARI Mehdi HADADZADEH Department of Biology Faculty of ScienceYazd UniversityYazd ***Iran Department of Cardiac Surgery Afshar HospitalShahid Sadoughi University of Medical SciencesYazd ***Iran

Objective:Transcription factor gata4 has significant roles in embryonic heart *** of gata4 appear to be responsible for a wide variety of congenital heart defects(CHD).Despite the high prevalence of gata4 mutations in CHD phenotypes,extensive studies have not been *** 3'-untranslated region(3'-UTR)of tho gata4 gene comprises regulatory motifs and microRNA binding sites that are critical for the appropriate gene expression,nuclear transportation,and regulation of translation,and stability of *** study aimed to evaluate the association between mutations in the 3'-UTR of the gata4 gene and CHD risk among Iranian patients.

关键词： congenital heart disease gata4 S'-untranslated region mutation in-silico analysis

miR-208a Promotes Apoptosis in H9c2 Cardiomyocytes by Targeting gata4

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Congenital Heart Disease 2021年第5期16卷 499-512页

作者： Liying Gong Hongkun Jiang Guangrong Qiu Kailai Sun Department of Medical Genetics School of Life SciencesChina Medical UniversityShenyangChina Department of Laboratory Medicine The People’s Hospital of Liaoning ProvinceShenyangChina Department of Laboratory Medicine The People’s Hospital of China Medical UniversityShenyangChina Department of Pediatrics The First Affiliated Hospital of China Medical UniversityShenyangChina

Background:microRNAs are crucial for cardiovascular development and are associated with congenital heart disease(CHD).Recent studies have shown that microRNAs play a role in heart development and is closely related to *** present study investigated the underlying mechanism of microRNA-208a(miR-208a)in“simple”*** and Methods:Reverse transcription-quantitative PCR(RT-qPCR)demonstrated miR-208a expression levels in children with CHD(n=27)compared with normal controls(n=29),in cardiomyocytes from embryo 10(E10)to post-birth(P7)and organs in adult rats in healthy *** of H9c2 cells after transfection with miR-208a detected by TUNEL assay.B-cell lymphoma(Bcl)-2,an anti-apoptotic gene,was detected by RT-qPCR,as well as *** 48h overexpression of miR-208a,gata4 was detected via western *** luciferase reporting system was used to identify the binding sites of miR-208a to ***:Expression of miR-208a was upregulated in the CHD group via the control group(p0.05).The present study proved that miR-208a binds directly to the 3´-UTR of gata4 at site 1,363-1,369 *** of gata4 decreased after miR-208a overexpression(pgata4,which may cause ***-208a may become a new biomarker or therapeutic target for CHD in the future.

关键词： Simple CHD miR-208a gata4 apoptosis Bcl-2

YQWY decoction reverses cardiac hypertrophy induced by TAC through inhibiting gata4 phosphorylation and MAPKs

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Chinese Journal of Natural Medicines 2019年第10期17卷 746-755页

作者： HUANG Jing-Jing XIE Yong LI He ZHANG Xiao-Xiao HUANG Qing ZHU Yao GU Ping JIANG Wei-Min The Affiliated Hospital of Nanjing University of Chinese Medicine Jiangsu Province Hospital of Traditional Chinese MedicineNanjing 210029China Department of Endocrinology Jinling HospitalSchool of MedicineNanjing UniversityNanjing 21002China

To investigate the effect of Yiqi Wenyang(YQWY) decoction on reversing cardiac hypertrophy induced by the transverse aortic constriction(TAC). Wistar rats aged 7-8 weeks were subjected to TAC surgery and then randomly divided into 4 groups(n = 5/group): Sham group, TAC group, low-dose group and high dose group. After 16-week intragastric administration of YQWY decoction, the effect of YQWY decoction on alleviating cardiomyocyte hypertrophy was examined by transthoracic echocardiography(TTE), hematoxylin/eosin(HE), wheat germ agglutinin(WGA) staining, enzyme linked immunosorbent assay(ELISA), Western blot(WB), immunohistochemistry(IHC) and immunofluorescence(IF), respectively. The results showed significant differences in left ventricle volume-diastole/systole(LV Vol d/s), N-terminal pro-B-type brain natriuretic peptide(NT-proBNP)(P gata binding protein 4(P-gata4)(P gata4 and mitogen activated protein kinases(MAPKs), as well as the reduced expression of the downstream targets of gata4, including ANP, BNP, and MYH7.

关键词： YQWY decoction Cardiac hypertrophy gata4 phosphorylation MAPKs

Cardiac Na^(+)-Ca^(2+) exchanger 1(ncx1h)is critical for the ventricular cardiomyocyte formation via regulating the expression levels of gata4 and hand2 in zebrafish

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Science China(Life Sciences) 2021年第2期64卷 255-268页

作者： Liming Chu Huimin Yin Lei Gao Li Gao Yu Xia Chiyuan Zhang Yi Chen Tingxi Liu Jijun Huang Kenneth R.Boheler Yong Zhou Huang-Tian Yang CAS Key Laboratory of Tissue Microenvironment and Tumor Laboratory of Molecular Cardiology and Laboratory of Development and DiseasesShanghai Institute of Nutrition and HealthUniversity of Chinese Academy of Sciences(CAS)CASShanghai 200031China Institute fo r Stem Cell and Regeneration CASBeijing 100101China State Key Laboratory fo r Medical Genomics Shanghai Institute of HematologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Department of Biomedical Engineering The Johns Hopkins UniversityBaltimoreMD 21205USA

Ca^(2+) signaling is critical for heart development;however,the precise roles and regulatory pathways of Ca^(2+) transport proteins in cardiogenesis remain largely ***-calcium exchanger 1(Ncx1)is responsible for Ca^(2+) efflux in *** is involved in cardiogenesis,while the mechanism is ***,using the forward genetic screening in zebrafish,we identified a novel mutation at a highly-conserved leucine residue in ncx1 gene(mutant^(LDD353)/ncx1h^(L154P))that led to smaller hearts with reduced heart rate and weak ***,the number of ventricular but not atrial cardiomyocytes was reduced in ncx1h^(L154P) *** defects were mimicked by knockdown or knockout of ***,ncx1h^(L154P) had cytosolic and mitochondrial Ca^(2+) overloading and Ca^(2+) transient suppression in ***,ncx1h^(L154P) and ncx1h morphants downregulated cardiac transcription factors hand2 and gata4 in the cardiac regions,while overexpression of hand2 and gata4 partially rescued cardiac defects including the number of ventricular *** findings demonstrate an essential role of the novel 154th leucine residue in the maintenance of Ncx1 function in zebrafish,and reveal previous unrecognized critical roles of the 154th leucine residue and Ncx1 in the formation of ventricular cardiomyocytes by at least partially regulating the expression levels of gata4 and hand2.

关键词： ncx1h Ca^(2+)transport protein ventricular cardiomyocyte formation hand2 gata4 zebrafish

Acetylation of H3K4,H3K9,and H3K27 mediated by p300 regulates the expression of gata4 in cardiocytes

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Genes & Diseases 2019年第3期6卷 318-325页

作者： Wei Zhou Dagui Jiang Jie Tian Lingjuan Liu Tiewei Lu Xupei Huang Huichao Sun Heart Centre Children’s Hospital of Chongqing Medical UniversityMinistry of Education Key Laboratory of Child Development and DisordersChongqing400014China China International Science and Technology Cooperation Base of Child Development and Critical Disorders Chongqing400014China Chongqing Key Laboratory of Pediatrics Chongqing400014China Department of Biomedical Science Charlie E.Schmidt College of MedicineFlorida Atlantic UniversityBoca RatonFLUSA Heart Centre Children’s Hospital of Chongqing Medical UniversityChongqing400014China

gata4 is a particularly important cardiogenic transcription factor and serves as a potent driver of *** progress in the field has made it clear that histone acetylation can influence gene expression through changing the structure of *** previous research had revealed that hypo-acetylation could repress gata4 expression in cardiocytes,however the underlying mechanism by which this occurred was still *** reveal the mechanism of histone acetylation involved in the regulation of gata4 transcription,we concentrated on P300,one of the important histone acetyltransferase associated with *** found that P300 participated in gata4 expression through regulating histone acetylation in embryonic mouse ***-mediated downregulation of P300 modulated the global acetylation of H3 and the acetylation of H3K4,H3K9,and H3K27 in gata4 and Tbx5 ***,there was an obvious inhibition of gata4 transcription,whereas Tbx5 was not ***,SGC-CBP30,the selective inhibitor of the bromodomain in CBP/P300,downregulated gata4 transcription by repressing the acetylation of H3K4,H3K9,and H3K27 in the gata4 *** together,our results identified that acetylation of H3K4,H3K9,and H3K27 mediated by P300 plays an important role in regulation of gata4 expression in cardiogenesis.

关键词： gata4 P300 Acetylation H3K4ac H3K9ac H3K27ac

Free fatty acid receptor 2 promotes cardiomyocyte hypertrophy by activating STAT3 and gata4

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Food Science and Human Wellness 2022年第2期11卷 405-417页

作者： Hui Gao Kunming Tian Xiaojun Feng Mengqing Yan Chen Gao Yisheng Jiang Chenhao Zhu Huzhe Zhu Xueping Liu Yingfu Peng Department of Pharmacology School of MedicineShaoxing UniversityShaoxing 312000China Department of Pharmacology School of MedicineJishou UniversityJishou 416000China Department of Environmental Toxicity Zunyi Medical UniversityZunyi 563006China The First Affi liated Hospital of USTC Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230002China Department of Pharmacology School of MedicineGuangXi University of science and TechnologyLiuzhou 545006China

Free fatty acids(FFAs)play important roles in cardiovascular *** have shown that it is an important way for FAs to exert biological effects through their own receptors besides directly participating biochemical reaction in *** fatty acid receptor 2(FFA2)can be activated by short-chain FAs and is involved in inflammatory reactions and lipid *** the known pathological changes caused by FFA2 are also implicated in cardiac hypertrophy,we hypothesized that FFA2 might be pathogenic in cardiac *** paper showed that FFA2 expression significantly increased in cardiac hypertrophy in vivo and in ***2 agonist 4-CMTB or TUG-1375 promoted the expression of the hypertrophy markers ANF and BNP and increased cell surface area in vitro,which was further strengthened by FFA2 overexpression,suggesting that FFA2 might contribute to cardiomyocyte ***,4-CMTB treatment or FFA2 overexpression combined with 4-CMTB treatment elevated the phosphorylation and transcriptional activity of gata4 and STAT3,which were inhibited by an ERK1/2 inhibitor,and gata4 and STAT3 knockdown inhibited the elevation of hypertrophy biomarkers in cardiomyocytes treated with *** together,these data indicate that FFA2 can enhance cardiomyocyte hypertrophy by activating STAT3 and gata4 via ERK1/2,providing a potential new target for therapy.

关键词： FFA2 Cardiac hypertrophy gata4 STAT3 ERK1/2

Mutational screening of affected cardiac tissues and peripheral blood cells identified novel somatic mutations in gata4 in patients with ventricular septal defect

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The Journal of Biomedical Research 2011年第6期25卷 425-430页

作者： Chunyan Cheng Yuan Lin Fan Yang Wenjing Wang Chong Wu Jingli Qin Xiuqin Shao Lei Zhou Department of Cardiology the First Affiliated Hospital of Nanjing Medical University Nanjing Jiangsu 210029 China Department of Human Population Genetics Institute of Molecular Medicine Peking University Beijing 100871 China.

The aim of this study was to examine how somatic mutations of the gata4 gene contributed to the genesis of ventricular septal defect （VSD）. The coding and intron-exon boundary regions of gata4 were sequenced of DNA samples from peripheral blood cells and cardiac tissues of twenty surgically treated probands with VSD. Seven novel heterozygous variants were detected in cardiac tissues from VSD patients, but they were not detected in the peripheral blood cells of VSD patients or in 500 healthy control samples. We replicated 14 single nucleotide polymorphisms （SNPs） reported in NCBI. Bioinformatics analysis was performed to analyze the possible mechanism by which mutations were linked to VSD. Among those variants, c. 1004C〉A （p.S335X） occurred in the highly conserved domain of gata4 and generated a termination codon, which led to the production of truncated gata4. The seven novel heterozygous gata4 mutations were only identified in cardiac tissues with VSD, suggesting that they are of somatic origin. A higher mutation rate in cardiac tissues than in peripheral blood cells implies that the genetic contribution to VSD may have been underestimated.

关键词： gata4 ventricular septal defect somatic mutation

gata4 and NKX2.5 gene analysis in Chinese Uygur patients with congenital heart disease

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Chinese Medical Journal 2009年第4期122卷 416-419页

作者： ZHANG Wei-min LI Xiao-feng MA Zhong-yuan ZHANG Jing ZHOU Si-hai LI Tao SHI Lin LI Zhong-zhi Cardiac Center Beijing Children's Hospital Affiliated to CapitalMedical University Beijing100045 China Department of Cardiac Surgery People's General Hospital of Xinjiang Autonomous Region Urumqi Xinjiang 830001 China Department of Surgery Urumqi First Hospital Urumqi Xinjiang830002 China Department of General Surgery First Hospital Affiliated to Xinjiang Medical University Urumqi Xinjiang 830054 China Department of Cardiology Capital Institute of PediatricsBeijing 100020 China

Background Congenital heart disease （CHD） is the most common developmental anomaly in newborns. The germline mutations in gata4 and NKX2.5 genes have been identified as responsible for CHD. The frequency of gata4 and NKX2.5 mutations in Chinese Uygur patients with CHD and the correlation between their genotype and CHD phenotype are unknown. Methods We examined the coding region of gata4 and NKX2,5genes in 62 Chinese Uygur patients with CHD and 117 Chinese Uygur individuals as the controls by denaturing high pedormance liquid chromatography （DHPLC） and sequencing. Results Two heterozygous missense mutations of c.1220C〉A and c.1273G〉A in gata4 gene, which cause the amino acid residue changes of P407Q and D425N in gata4, were found in a patient with tetralogy of Fallot and a patient with ventricular septal defect, respectively. The two patients did not have atrioventricular conduct defects or non-cardiac abnormalities. The two mutations are expected to affect the protein function. There were no reported NKX2.5 mutations in the patients. Conclusion Our results provided the primary data on CHD phenotype associated with gata4 mutation in the Chinese Uygur population.

关键词： gata4 NKX2.5 congenital heart disease gene mutation

心力衰竭患者Circ-PALLD的高表达受转录因子gata4的转录调控

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南方医科大学学报 2023年第8期43卷 1371-1378页

作者：黄卓曾振宇李佳蔡蕊贺文霞胡淑婷宁夏医科大学基础医学院宁夏银川750004 海军军医大学附属长海医院心内科上海200433

目的确定环状RNA-Circ-PALLD在心力衰竭中的表达变化;初步探究Circ-PALLD的生物学发生。方法通过现有分析人和鼠心衰样本中的二代测序结果,确定候选CircRNAs;PCR扩增后进行Sanger一代测序,比对测序结果,确定对应CircRNA的反向剪接方式;... 详细信息

目的确定环状RNA-Circ-PALLD在心力衰竭中的表达变化;初步探究Circ-PALLD的生物学发生。方法通过现有分析人和鼠心衰样本中的二代测序结果,确定候选CircRNAs;PCR扩增后进行Sanger一代测序,比对测序结果,确定对应CircRNA的反向剪接方式;纳入我院心衰患者8例,提取RNA后进行PCR扩增,检测CircRNAs与线性RNA的表达;RT-qPCR检测在衰竭心肌中Circ-PALLD与PALLD的表达水平;生物信息学预测可能调控基因PALLD的转录因子;设计并合成针对gata4的siRNA,确定转录因子gata4对PALLD的调控作用。结果Sanger测序和序列比对验证了Circ-VWA8,Circ-VMP1,Circ-PRDM5,Circ-PLCL2,Circ-PALLD,Circ-NFATC3,Circ-MLIP,Circ-FAM208A,Circ-ANKIB1,Circ-AGTPBP1的反向剪接,证明了其成环性,确定了反向剪接的外显子排列;半定量PCR结果表明Circ-PALLD,Circ-NFATC3和Circ-AGTPBP1在心衰患者的心肌组织中表达水平明显增加,而其中线性PALLD的表达水平明显降低,提示Circ-PALLD在慢性心衰中的潜在作用;通过生物信息学分析后发现PALLD的转录可能受转录因子gata4所调控;RT-qPCR结果表明,Circ-PALLD在衰竭心肌中表达水平明显升高,而PALLD表达水平明显降低,其结果与半定量PCR结果一致;在原代乳鼠心肌细胞中敲降gata4后Circ-PALLD与PALLD表达水平均降低。结论Circ-PALLD在心衰中高表达,可作为慢性心衰的新型分子标志物,且转录因子gata4在PALLD的转录中或有重要作用,因此Circ-PALLD可能为心力衰竭发生的分子机制提供新的研究方向并且为心衰治疗提供了潜在的药物靶点。

关键词：心力衰竭 gata4 Circ-PALLD 生物标志物