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1.
Med Eng Phys ; 126: 104157, 2024 04.
Article in English | MEDLINE | ID: mdl-38621853

ABSTRACT

Both ageing and hypertension are clinical factors that may lead to a higher propensity for dissection or rupture of ascending thoracic aortic aneurysms (ATAAs). This study sought to investigate effect of valve morphology on regional delamination strength of ATAAs in the elderly hypertensive patients. Whole fresh ATAA samples were harvested from 23 hypertensive patients (age, 71 ± 8 years) who underwent elective aortic surgery. Peeling tests were performed to measure region-specific delamination strengths of the ATAAs, which were compared between patients with bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV). The regional delamination strengths of the ATAAs were further correlated with patient ages and aortic diameters for BAV and TAV groups. In the anterior and right lateral regions, the longitudinal delamination strengths of the ATAAs were statistically significantly higher for BAV patients than TAV patients (33 ± 7 vs. 23 ± 8 mN/mm, p = 0.01; 30 ± 7 vs. 19 ± 9 mN/mm, p = 0.02). For both BAV and TAV patients, the left lateral region exhibited significantly higher delamination strengths in both directions than the right lateral region. Histology revealed that disruption of elastic fibers in the right lateral region of the ATAAs was more severe for the TAV patients than the BAV patients. A strong inverse correlation between longitudinal delamination strength and age was identified in the right lateral region of the ATAAs of the TAV patients. Results suggest that TAV-ATAAs are more vulnerable to aortic dissection than BAV-ATAAs for the elderly hypertensive patients. Regardless of valve morphotypes, the right lateral region may be a special quadrant which is more likely to initiate dissection when compared with other regions.


Subject(s)
Aortic Aneurysm, Thoracic , Aortic Aneurysm , Bicuspid Aortic Valve Disease , Hypertension , Humans , Aged , Middle Aged , Aortic Valve , Aortic Aneurysm, Thoracic/complications , Aortic Aneurysm, Thoracic/pathology , Aorta/pathology , Aortic Aneurysm/pathology , Bicuspid Aortic Valve Disease/pathology , Hypertension/complications , Hypertension/pathology
2.
Aging (Albany NY) ; 16(6): 5651-5675, 2024 03 20.
Article in English | MEDLINE | ID: mdl-38517374

ABSTRACT

Heart failure (HF) is a serious global health issue that demands innovative treatment approaches. In this study, we collected samples from 4 HF patients before and after MSC therapy and performed scRNA-seq. After the MSC therapy, the proportion of CD14+ monocytes decreased significantly in both the treatment response and non-response groups, with a more pronounced decrease in the treatment response group. The therapy-response and non-response group were clearly separated in the UMAP plot, while the CD14+ monocytes in the therapy-response group before and after MSC therapy were very similar, but there were significant differences in the non-response group. By further performing NMF analysis, we identified 11 subsets of CD14+ monocytes. More importantly, we identified a therapy-related CD14+ monocyte subpopulation. The predictive model based on CD14+ monocytes constructed by machine learning algorithms showed good performance. Moreover, genes such as FOS were highly enriched in the therapy-related CD14+ monocytes. The SCENIC analysis revealed potential regulatory factors for this treatment-responsive CD14+ monocytes, and FOS/JUN were identified as potential core indicators/regulators. Finally, HF patients were divided into three groups by NMF analysis, and the therapy-responsive CD14+ monocyte characteristics were differentially activated among the three groups. Together, this study identifies treatment-responsive CD14+ monocytes as a crucial biomarker for assessing the suitability of MSC therapy and determining which HF patients could benefit from it. This provides new clues for further investigating the therapeutic mechanisms of MSC therapy, offering beneficial insights for personalized treatment and improving prognosis in HF patients.


Subject(s)
Heart Failure , Mesenchymal Stem Cell Transplantation , Humans , Biomarkers , Heart Failure/genetics , Heart Failure/therapy , Monocytes , RNA-Seq
3.
ESC Heart Fail ; 10(4): 2541-2549, 2023 08.
Article in English | MEDLINE | ID: mdl-37308095

ABSTRACT

AIMS: We sought to investigate the relationship between circulating tissue plasminogen activator (t-PA) level and long-term outcomes in stable coronary artery disease patients with or without aortic valve sclerosis (AVSc). METHODS AND RESULTS: Serum levels of t-PA were determined in 347 consecutive stable angina patients with (n = 183) or without (n = 164) AVSc. Outcomes were prospectively recorded as planned clinic evaluations every 6 months up to 7 years. The primary endpoint was a composite of cardiovascular death and rehospitalization due to heart failure. The secondary endpoint included all-cause mortality, cardiovascular death, and rehospitalization due to heart failure. Serum t-PA was significantly higher in AVSc than in non-AVSc patients (2131.22 pg/mL vs. 1495.85 pg/mL, P < 0.001). For patients with AVSc, those with t-PA level above the median (>1840.68 pg/mL) were more likely to meet the primary and secondary endpoints (all P < 0.001). After adjusting for potential confounding factors, serum t-PA level remained significantly predictive for each endpoint in the Cox proportional hazard models. The prognostic value of t-PA was good, with an AUC-ROC of 0.753 (P < 0.001). The combination of t-PA with traditional risk factors improved the risk reclassification of AVSc patients, with a net reclassification index of 0.857 and an integrated discrimination improvement of 0.217 (all P < 0.001). However, for patients without AVSc, both primary and secondary endpoints were similar, irrespective of t-PA levels. CONCLUSIONS: Elevated circulating t-PA confers an increased risk for poor long-term clinical outcomes in stable coronary artery disease patients with AVSc.


Subject(s)
Coronary Artery Disease , Heart Failure , Humans , Coronary Artery Disease/complications , Coronary Artery Disease/diagnosis , Tissue Plasminogen Activator , Prognosis , Aortic Valve , Sclerosis/pathology , Heart Failure/pathology
4.
J Biomech ; 154: 111615, 2023 06.
Article in English | MEDLINE | ID: mdl-37178496

ABSTRACT

Hypertension is a major predisposing factor to initiate thoracic aortopathy. The objective of this study is to investigate effect of hypertension on delamination and tensile strength of ascending thoracic aortic aneurysms (ATAAs). A total of 35 fresh ATAA samples were harvested from 19 hypertensive and 16 non-hypertensive patients during elective aortic surgery. Peeling tests with two extension rates were performed to determine delamination strength, while uniaxial tensile (UT) tests were employed to measure failure stresses. The delamination strength and failure stresses of the ATAAs were further correlated with patient ages for hypertensive and non-hypertensive groups. The delamination strength to peel apart the ATAA tissue along the longitudinal direction was statistically significantly lower for the hypertensive patients than that of the non-hypertensive patients (35 ± 11 vs. 49 ± 9 mN/mm, p = 0.02). A higher delamination strength was measured if peeling was performed with a higher extension rate. The circumferential failure stresses were significantly lower for the hypertensive ATAAs than those of the non-hypertensive ATAAs (1.03 ± 0.27 vs. 1.43 ± 0.38 MPa, p = 0.02). Histology showed that laminar structures of elastic fibers were mainly disrupted in the hypertensive ATAAs. The longitudinal delamination strength of the ATAAs was significantly decreased and strongly correlated with ages for the hypertensive patients. Strong inverse correlations were also identified between the circumferential and longitudinal failure stresses of the ATAAs and ages for the hypertensive patients. Results suggest that the ATAAs of the elderly hypertensive patients may have a higher propensity for dissection or rupture. The dissection properties of the ATAA tissue are rate dependent.


Subject(s)
Aortic Aneurysm, Thoracic , Hypertension , Humans , Aged , Tensile Strength , Biomechanical Phenomena , Aorta , Aorta, Thoracic , Stress, Mechanical
5.
Article in English | MEDLINE | ID: mdl-36951538

ABSTRACT

Acute type A aortic dissection complicated by carotid artery is associated with a high risk of perioperative stroke. We reported a case of application of hybrid aortic arch debranching procedure in acute type A aortic dissection complicated by right carotid artery occlusion, which resulted in no neurological complications after operation and patent carotid artery after discharging.

6.
Stem Cells Int ; 2023: 6256115, 2023.
Article in English | MEDLINE | ID: mdl-36970596

ABSTRACT

Overactive inflammatory responses contribute to progressive cardiac dysfunction after myocardial infarction (MI). Mesenchymal stem cell (MSC) has generated significant interest as potent immune modulators that can regulate excessive immune responses. We hypothesized that intravenous (iv) administration of human umbilical cord-derived MSC (HucMSC) exerts systemic and local anti-inflammation effects, leading to improved heart function after MI. In murine MI models, we confirmed that single iv administration of HucMSC (30 × 104) improved cardiac performance and prevented adverse remodeling after MI. A small proportion of HucMSC is trafficked to the heart, preferentially in the infarcted region. HucMSC administration increased CD3+ T cell proportion in the periphery while decreased T cell proportion in both infarcted heart and mediastinal lymph nodes (med-LN) at 7-day post-MI, indicating a systematic and local T cell interchange mediated by HucMSC. The inhibitory effects of HucMSC on T cell infiltration in the infarcted heart and med-LN sustained to 21-day post-MI. Our findings suggested that iv administration of HucMSC fostered systemic and local immunomodulatory effects that contributed to the improvement of cardiac performance after MI.

7.
Chem Biodivers ; 20(2): e202200730, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36639922

ABSTRACT

Adverse cardiac remodeling may lead to the development and progression of heart failure, which is lack of effective clinical treatment. Ginsenoside Rg1 (GRg1), a primary ingredient of Panax ginseng, protects against diverse cardiovascular disease, but its effects on cardiac remodeling remain unclear. Thus, we investigated the protective effect and mechanism of GRg1 on cardiac remodeling after myocardial infarction. GRg1 significantly ameliorated cardiac remodeling in mice with left anterior descending coronary artery ligation, reflected by reduced left ventricular dilation and decreased cardiac fibrosis, accompanied by improved cardiac function. Mechanistically, GRg1 considerably increased mitophagosomes formation, ameliorated cardiac mitochondria damage, and enhanced SIRT1/PINK1/Parkin-mediated mitophagy during cardiac remodeling. Consistently, GRg1 increased cell viability and attenuated apoptosis and fibrotic responses in H2 O2 -treated H9c2 cells by promoting the SIRT1/PINK1/Parkin axis. Furthermore, SIRT1-specific inhibitor (EX527) or the use of small interfering RNA against Parkin abolished the protective effect of GRg1 in vitro. These findings reveal a novel mechanism of GRg1 alleviating cardiac remodeling via enhancing SIRT1/PINK1/Parkin-mediated mitophagy.


Subject(s)
Heart Failure , Mitophagy , Mice , Animals , Mitophagy/physiology , Protein Kinases , Sirtuin 1 , Ventricular Remodeling , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/pharmacology
8.
Exp Biol Med (Maywood) ; 248(1): 52-60, 2023 01.
Article in English | MEDLINE | ID: mdl-36151748

ABSTRACT

The calcific aortic valve disease (CAVD) develops as an aortic valve sclerosis and progresses to an advanced form of stenosis. In many biological fields, bioinformatics becomes a fundamental component. The key mechanisms involved in CAVD are discovered with the use of bioinformatics to investigate gene function and pathways. We downloaded the original data (GSE51472) from the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/). After standardization, 2978 differentially expressed genes (DEGs) were identified from the data sets GSE51472 containing samples from normal, calcified, and sclerotic aortic valves. Analysis of DEGs based on the series test of clusters (STCs) revealed the two most significant patterns. Based on the result of the STC, the functional enrichment analysis of gene ontology (GO) was conducted to investigate the molecular function (MF), biological process (BP), and cell compound (CC) of the DEGs. With a p value of 0.01, DEGs associated with "chronic inflammation," "T-cell receptor complexes," and "antigen binding" had the highest significance within BP, CC, and MF. DEG enrichment in signaling pathways was analyzed using KEGG pathway enrichment. Using a p < 0.05 level of significance, the most enriched biological pathways related to CAVD were "Chemokine signaling pathway," "Cytokine-cytokine receptor interaction," "Tuberculosis," "PI3K-Akt signaling pathway," and "Transcriptional misregulation in cancer." Finally, the construction of gene co-expression networks and pathway networks illustrated the pathogensis of CAVD. TLR2, CD86, and TYROBP were identified as hub genes for the development of CAVD. Moreover, "MAPK signaling pathway," "Apoptosis," and "Pathways in cancer" were regarded as the core pathways among the samples of normal, sclerotic and calcified aortic valve samples.


Subject(s)
Aortic Valve Stenosis , Aortic Valve , Humans , Phosphatidylinositol 3-Kinases , Aortic Valve Stenosis/genetics , Computational Biology , Gene Expression Profiling
9.
Stem Cell Res Ther ; 13(1): 247, 2022 06 11.
Article in English | MEDLINE | ID: mdl-35690805

ABSTRACT

BACKGROUND: Human umbilical cord-derived mesenchymal stem cells (HucMSCs) have been recognized as a promising cell for treating myocardial infarction (MI). Inflammatory response post MI is critical in determining the cardiac function and subsequent adverse left ventricular remodeling. However, the local inflammatory effect of HucMSCs after intramyocardial injection in murine remains unclear. METHODS: HucMSCs were cultured and transplanted into the mice after MI surgery. Cardiac function of mice were analyzed among MI-N.S, MI-HucMSC and MI-HucMSC-C-C Motif Chemokine receptor 5 (CCR5) antagonist groups, and angiogenesis, fibrosis and hypertrophy, and immune cells infiltration of murine hearts were evaluated between MI-N.S and MI-HucMSC groups. We detected the expression of inflammatory cytokines and their effects on CD4+ T cells migration. RESULTS: HucMSCs treatment can significantly improve the cardiac function and some cells can survive at least 28 days after MI. Intramyocardial administration of HucMSCs also improved angiogenesis and alleviated cardiac fibrosis and hypertrophy. Moreover, we found the much higher numbers of CD4+ T cells and CD4+FoxP3+ regulatory T cells (Tregs) in the heart with HucMSCs than that with N.S treatment on day 7 post MI. In addition, the protein level of C-C Motif Chemokine Ligand 5 (CCL5) greatly increased in HucMSCs treated heart compared to MI-N.S group. In vitro, HucMSCs inhibited CD4+ T cells migration and addition of CCL5 antibody or CCR5 antagonist significantly reversed this effect. In vivo results further showed that addition of CCR5 antagonist can reduce the cardioprotective effect of HucMSCs administration on day 7 post MI injury. CONCLUSION: These findings indicated that HucMSCs contributed to cardiac functional recovery and attenuated cardiac remodeling post MI. Intramyocardial injection of HucMSCs upregulated the CD4+FoxP3+ Tregs and contributed to the migration of CD4+ T cells into the injured heart via CCL5/CCR5 pathway.


Subject(s)
Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Myocardial Infarction , Animals , CD4-Positive T-Lymphocytes , Chemokine CCL5/metabolism , Forkhead Transcription Factors/metabolism , Humans , Hypertrophy/metabolism , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/metabolism , Mice , Myocardial Infarction/metabolism , Myocardial Infarction/therapy , Receptors, CCR5/genetics , Receptors, CCR5/metabolism , Umbilical Cord
10.
BMC Cardiovasc Disord ; 21(1): 562, 2021 11 22.
Article in English | MEDLINE | ID: mdl-34809569

ABSTRACT

BACKGROUND: Aberrant right subclavian artery (ARSA) with associated Kommerell diverticulum (KD) is a rare congenital aortic disease. KD patients have a high risk of rupture, dissection, and compression of adjacent structures. Although several treatment options have been proposed (traditional surgery, hybrid operation, and endovascular intervention), a consensus regarding optimal surgical management has not yet been established. CASE PRESENTATION: A case of successful hybrid repair of distal aortic arch dissection aneurysm by dissecting KD and ARSA with debranching of right and left common carotid arteries, left subclavian artery, and stent grafting was presented. CONCLUSIONS: The hybrid operation is suitable for elderly patients or those with high risks. Along with intervention, the hybrid operation needs to be developed as a minimally invasive method.


Subject(s)
Aortic Aneurysm/surgery , Aortic Diseases/surgery , Aortic Dissection/surgery , Blood Vessel Prosthesis Implantation , Cardiovascular Abnormalities/surgery , Diverticulum/surgery , Subclavian Artery/abnormalities , Adult , Aortic Dissection/diagnostic imaging , Aortic Dissection/etiology , Aortic Aneurysm/diagnostic imaging , Aortic Aneurysm/etiology , Aortic Diseases/congenital , Aortic Diseases/diagnostic imaging , Aortography , Blood Vessel Prosthesis , Blood Vessel Prosthesis Implantation/adverse effects , Cardiovascular Abnormalities/complications , Cardiovascular Abnormalities/diagnostic imaging , Computed Tomography Angiography , Diverticulum/congenital , Diverticulum/diagnostic imaging , Humans , Male , Stents , Subclavian Artery/diagnostic imaging , Subclavian Artery/surgery , Treatment Outcome
11.
Biomater Sci ; 9(4): 1088-1103, 2021 Feb 21.
Article in English | MEDLINE | ID: mdl-33332490

ABSTRACT

Studies of nanomedicine have achieved dramatic progress in recent decades. However, the main challenges that traditional nanomedicine has to overcome include low accumulation at target sites and rapid clearance from the blood circulation. An interesting approach using cell membrane coating technology has emerged as a possible way to overcome these limitations, owing to the enhanced targeted delivery and reduced immunogenicity of cell membrane moieties. Mesenchymal stem cell (MSC) therapy has been investigated for treating various diseases, ranging from inflammatory diseases to tissue damage. Recent studies with engineered modified MSCs or MSC membranes have focused on enhancing cell therapeutic efficacy. Therefore, bioengineering strategies that couple synthetic nanoparticles with MSC membranes have recently received much attention due to their homing ability and tumor tropism. Given the various membrane receptors on their surfaces, MSC membrane-coated nanoparticles are an effective method with selective targeting properties, allowing entry into specific cells. Here, we review recent progress on the use of MSC membrane-coated nanoparticles for biomedical applications, particularly in the two main antitumor and anti-inflammatory fields. The combination of a bioengineered cell membrane and synthesized nanoparticles presents a wide range of possibilities for the further development of targeted drug delivery, showing the potential to enhance the therapeutic efficacy for treating various diseases.


Subject(s)
Mesenchymal Stem Cells , Nanoparticles , Pharmaceutical Preparations , Drug Delivery Systems , Nanomedicine
12.
J Biomech ; 100: 109592, 2020 02 13.
Article in English | MEDLINE | ID: mdl-31911049

ABSTRACT

Effect of diabetes mellitus (DM) on the dissection properties of thoracic aortas remains largely unclear and relevant biomechanical analysis is lacking. In the present study forty adult rabbits (1.6-2.2 kg) were collected and type 1 diabetic rabbit model was induced by injection of alloxan. A total of 10 control and 30 diabetic (with different time exposure to diabetic condition) rabbit descending thoracic aortas were harvested. Peeling tests were performed to quantitatively determine force/width values and dissection energy in the control and diabetic aortas. Histological and mass fraction analyses were performed to characterize the dissected morphology and to quantify dry weight percentages of elastin and collagen. The resisting force/width values were significantly higher for the diabetic thoracic aortas (in 8 weeks) than those of the control thoracic aortas (axial: 26.1 ± 4.0 vs. 20.5 ± 3.1 mN/mm, p = 0.04; circ: 19.7 ± 2.8 vs. 15.3 ± 1.9 mN/mm, p = 0.03). There was a higher resistance to the dissection in both axial and circumferential directions for the diabetic aortas. The dissection energy generated by axial and circumferential peeling of the diabetic aortas (in 6 and 8 weeks) was statistically significantly higher than that of the control aortas (axial: 5.6 ± 0.7 vs. 4.3 ± 0.5 mJ/cm2, p = 0.02; circ: 3.9 ± 0.3 vs. 3.2 ± 0.3 mJ/cm2, p = 0.02). Histology showed that dissection mainly occurred in the aortic media and the dissected surfaces were close to external elastic lamina for some specimens. The mass fractions of collagen within the diabetic aortas increased significantly as compared to the control aortas, whereas no significant change was found for that of elastin. Our data suggest that the experimentally induced DM may lead to a lower propensity of dissection for the rabbit thoracic aortas. The dissection properties of the rabbit thoracic aortas vary with time exposed to diabetic condition.


Subject(s)
Aorta, Thoracic , Aortic Diseases/complications , Diabetes Mellitus, Experimental/complications , Animals , Aorta, Thoracic/metabolism , Aorta, Thoracic/physiopathology , Aortic Diseases/metabolism , Aortic Diseases/physiopathology , Biomechanical Phenomena , Collagen/metabolism , Male , Rabbits
13.
DNA Cell Biol ; 32(12): 708-16, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24083357

ABSTRACT

Congenital heart disease (CHD) is the most common form of birth defect and is the leading noninfectious cause of infant death. A growing body of evidence demonstrates that genetic risk factors are involved in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disease and the genetic defects underlying CHD in an overwhelming majority of patients remain unclear. In this study, the whole coding region and splice junction sites of the PITX2c gene, which encodes variant 3 of paired-like homeodomain transcription factor 2 crucial for normal cardiovascular morphogenesis, were sequenced in 382 unrelated patients with CHD, and 2 novel heterozygous mutations, p.W147X and p.N153D, were identified in 2 unrelated patients with CHD, respectively, including a 1-year-old male patient with double outlet right ventricle in combination with ventricular septal defect and a 4-year-old female patient with ventricular septal defect. The mutations were absent in 400 control chromosomes and were both predicted to be disease-causing by MutationTaster. Multiple alignments of PITX2c proteins across species displayed that the altered amino acids were completely conserved evolutionarily. Functional analysis revealed that the mutated PITX2c proteins were associated with a significantly reduced transactivational activity compared with their wild-type counterpart. These findings provide a novel insight into the molecular mechanisms implicated in CHD, suggesting potential implications for the antenatal prophylaxis and allele-specific treatment of CHD.


Subject(s)
Heart Defects, Congenital/genetics , Homeodomain Proteins/genetics , Mutation , Transcription Factors/genetics , Adult , Amino Acid Sequence , Animals , Child, Preschool , China/epidemiology , Female , Genetic Variation , Heart Defects, Congenital/epidemiology , Homeodomain Proteins/chemistry , Humans , Infant , Male , Middle Aged , Phenotype , Prevalence , Sequence Alignment , Transcription Factors/chemistry , Homeobox Protein PITX2
14.
Hum Mutat ; 34(12): 1662-71, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24000169

ABSTRACT

Tetralogy of Fallot (TOF) represents the most common form of cyanotic congenital heart disease and accounts for significant morbidity and mortality in humans. Emerging evidence has implicated genetic defects in the pathogenesis of TOF. However, TOF is genetically heterogeneous and the genetic basis for TOF in most patients remains unclear. In this study, the GATA4 gene were sequenced in 52 probands with familial TOF, and three novel heterozygous mutations, including A9P and L51V both located in the putative first transactivational domain and N285S in the C-terminal zinc finger, were identified in three probands, respectively. Genetic analysis of the pedigrees demonstrated that in each family the mutation cosegregated with TOF with complete penetrance. The missense mutations were absent in 800 control chromosomes and the altered amino acids were highly conserved evolutionarily. Functional analysis showed that the GATA4 mutants were consistently associated with diminished DNA-binding affinity and decreased transcriptional activity. Furthermore, the N285S mutation completely disrupted the physical interaction between GATA4 and TBX5. To our knowledge, this report associates GATA4 loss-of-function mutations with familial TOF for the first time, providing novel insight into the molecular mechanism involved in TOF and suggesting potential implications for the early prophylaxis and allele-specific therapy of TOF.


Subject(s)
GATA4 Transcription Factor/genetics , Mutation , Tetralogy of Fallot/genetics , Adolescent , Adult , Alleles , Amino Acid Sequence , Cell Nucleus/metabolism , Child , Child, Preschool , DNA Mutational Analysis , Female , GATA4 Transcription Factor/chemistry , GATA4 Transcription Factor/metabolism , Genotype , Humans , Infant , Male , Middle Aged , Molecular Sequence Data , Pedigree , Phenotype , Protein Binding , Protein Transport , Sequence Alignment , T-Box Domain Proteins/metabolism , Tetralogy of Fallot/diagnosis , Transcription, Genetic , Young Adult
16.
DNA Cell Biol ; 31(11): 1610-7, 2012 Nov.
Article in English | MEDLINE | ID: mdl-23020118

ABSTRACT

Congenital heart disease (CHD) is the most common form of developmental malformation and is the leading noninfectious cause of infant mortality. Emerging evidence indicates that genetic defects are involved in the pathogenesis of CHD. Nevertheless, CHD is genetically heterogeneous, and the molecular basis for CHD in a majority of patients remains unknown. In this study, the whole coding region of GATA6, a gene encoding a zinc-finger transcription factor crucial for normal cardiogenesis, was sequenced in 380 unrelated patients with CHD. The relatives of the index patients harboring the identified mutations and 200 unrelated control individuals were subsequently genotyped. The functional effect of the mutations was characterized using a luciferase reporter assay system. As a result, two novel heterozygous GATA6 mutations, p.D404Y and p.E460X, were identified in two families with ventricular septal defect and tetralogy of Fallot, respectively. The mutations co-segregated with CHD in the families with complete penetrance, and were absent in 400 control chromosomes. Functional analysis demonstrated that the mutated GATA6 proteins were associated with significantly decreased transactivational activity in comparison with their wild-type counterpart. These findings provide novel insight into the molecular mechanism implicated in CHD, suggesting potential implications for the early prophylaxis and personalized treatment of CHD.


Subject(s)
GATA6 Transcription Factor/genetics , Heart Defects, Congenital/genetics , Mutation , Tetralogy of Fallot/genetics , Adolescent , Adult , Asian People/genetics , Base Sequence , Child , Child, Preschool , China , Cohort Studies , DNA Mutational Analysis , Family Health , Female , Genetic Predisposition to Disease/genetics , Genotype , HEK293 Cells , Heart Defects, Congenital/ethnology , Humans , Infant , Male , Pedigree , Tetralogy of Fallot/ethnology , Young Adult
17.
Int J Mol Med ; 28(4): 557-64, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21637914

ABSTRACT

Ventricular septal defect (VSD) is the most common type of cardiovascular developmental anomaly and is an important risk factor for the substantially increased morbidity and mortality in newborns. Aggregating evidence implicates genetic defects in the pathogenesis of congenital VSD. However, VSD is genetically heterogeneous and the genetic determinants for VSD in most patients remain to be identified. In this study, the whole coding region of the GATA4 gene, which encodes a zinc-finger transcription factor pivotal to cardiogenesis, was initially sequenced in 210 unrelated patients with VSD. The relatives of the index patient carrying the identified mutation and 200 unrelated ethnically-matched healthy individuals used as controls were subsequently genotyped. The functional effect of the mutant GATA4 was characterized in contrast to its wild-type counterpart using a luciferase reporter assay system. A novel heterozygous GATA4 mutation, p.G296R, was identified in a family with VSD inherited as an autosomal dominant trait. Absent in 200 control individuals, the mutation co-segregated with VSD in the family with 100% penetrance and was completely conserved evolutionarily across species. Functional analysis displayed that the p.G296R mutation of GATA4 was associated with a decreased transcriptional activity. The findings expand the spectrum of mutations in GATA4 linked to VSD and provide more insight into the molecular mechanism involved in VSD. The results of the present study imply the potential implications in the genetic diagnosis and gene-specific therapy of this common malformation in infancy.


Subject(s)
GATA4 Transcription Factor/genetics , Heart Septal Defects, Ventricular/genetics , Child, Preschool , Female , Humans , Male , Mutation/genetics , Pedigree
18.
Int J Mol Med ; 27(3): 369-75, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21165553

ABSTRACT

Ventricular septal defect (VSD) is the most common cardiovascular malformation and an important contributor to the substantial morbidity and mortality in infancy. Growing evidence suggests that genetic defects play important roles in the pathogenesis of congenital VSD. However, VSD is of great genetic heterogeneity and the genetic basis for VSD in the majority of the patients remains largely unhnown. In this study, the entire coding region of the NKX2-5 gene, which encodes a homeodomain-containing transcription factor crucial to cardiogenesis, was initially sequenced in 136 unrelated patients with VSD. The relatives of a proband harboring the identified mutation and 200 unrelated control individuals were genotyped. The functional characteristic of the mutant transcription factor was analyzed in contrast to its wild-type counterpart using a luciferase reporter assay system. A novel heterozygous NKX2-5 mutation, p.P59A, was identified in a family with autosomal dominant inherited VSD. Absent in the 200 control individuals, the mutation was highly conserved evolutionarily and co-segregated with VSD in the family with complete penetrance. Functional analysis revealed that the p.P59A mutation of NKX2-5 was associated with a decreased transcriptional activity. These findings expand the spectrum of the mutations in NKX2-5 linked to VSD and provide new insight into the molecular mechanisms involved in VSD. The resuls of the present study may have potential implications in the genetic diagnosis and gene-specific therapy of this common childhood disease.


Subject(s)
Amino Acid Substitution , Genetic Diseases, Inborn/genetics , Heart Septal Defects, Ventricular/genetics , Homeodomain Proteins/genetics , Mutation, Missense , Transcription Factors/genetics , Child , Child, Preschool , Female , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/metabolism , Genetic Diseases, Inborn/therapy , Heart Septal Defects, Ventricular/diagnosis , Heart Septal Defects, Ventricular/metabolism , Heart Septal Defects, Ventricular/therapy , Homeobox Protein Nkx-2.5 , Homeodomain Proteins/metabolism , Humans , Male , Transcription Factors/metabolism
19.
Zhonghua Xin Xue Guan Bing Za Zhi ; 38(5): 429-34, 2010 May.
Article in Chinese | MEDLINE | ID: mdl-20654103

ABSTRACT

OBJECTIVE: To screen the gene GATA4 for novel mutations associated with congenital atrial septal defect (ASD). METHODS: The clinical data and peripheral venous blood specimen from 85 unrelated subjects with congenital ASD were collected and analyzed in contrast to 200 healthy individuals. The coding exons and the exon/intron boundaries of GATA4 gene were amplified by polymerase chain reaction and sequenced using the di-deoxynucleotide chain termination procedure. The obtained sequences were aligned with those publicized in GenBank with the help of programme BLAST to identify the sequence variations. The software Clustal W was applied to analysis of the conservation of altered amino acids. RESULTS: Three novel heterozygous missense GATA4 mutations were identified in 3 of 85 ASD patients, respectively. Namely, the triplet substitutions of ATG for GTG at codon 267, GCC for ACC at codon 354, and CAA for CCA at codon 407, predicting the conversions of valine into methionine at amino acid residue 267 (V267M), threonine into alanine at amino acid residue 354 (T354A), and proline into glutamine at amino acid residue 407 (P407Q), were identified. No mutation was detected in 200 healthy controls. A cross-species alignment of GATA4 encoded protein sequences showed that the valine at amino acid residue 267 and proline at amino acid residue 407 were completely conserved evolutionarily. CONCLUSION: Three novel heterozygous missense GATA4 mutations were identified in patients with congenital ASD, which reveals new molecular etiology responsible for ASD, and contributes to the early prophylaxis and therapy for ASD.


Subject(s)
GATA4 Transcription Factor/genetics , Heart Septal Defects, Atrial/genetics , Mutation, Missense , Base Sequence , Case-Control Studies , DNA Mutational Analysis , Genetic Testing , Humans
20.
Zhonghua Yi Xue Za Zhi ; 90(10): 667-71, 2010 Mar 16.
Article in Chinese | MEDLINE | ID: mdl-20450724

ABSTRACT

OBJECTIVE: To identify the novel genetic determinants in patients with congenital heart disease (CHD). METHODS: The clinical data and peripheral venous blood samples from 120 unrelated individuals with idiopathic CHD were collected and evaluated compared to 100 unrelated healthy controls. The complete coding exons and the partial flanking introns of GATA4 gene were amplified by polymerase chain reaction and sequenced by di-deoxynucleotide chain termination. The generated sequences were aligned with those retrieved from GenBank with the aid of programme BLAST to identify the sequence variations. The software Clustal W was utilized to analyze the conservation of altered amino acids. RESULTS: Three novel heterozygous missense GATA4 mutations were identified in 3 of 120 CHD cases. Namely, the triplet substitutions of AGA for AGC at codon 90, GAG for GAC at codon 95, and AAT for AAG at codon 329, predicting the conversions of serine into arginine at amino acid residue 90 (S90R), aspartic acid into glutamic acid at amino acid residue 95 (D95E) and lysine into asparagine at amino acid residue 329 (K329N), were detected. None of these three mutations were probed in 100 controls. A cross-species alignment of GATA4 encoded protein sequences displayed that the lysine at amino acid residue 329 was completely conserved evolutionarily. Additionally, a single nucleotide polymorphism c. 99G>T was observed. However, the polymorphic frequency distribution in CHD patients was not statistically different from that in controls (for genotypes, chi(2) = 0.2640, P = 0.6074; for alleles, chi(2) = 0.2514, P = 0.6161). CONCLUSION: The idiopathic CHD has a marked heterogeneity and the mutated GATA4 gene may be responsible for CHD in a subset of patients.


Subject(s)
GATA4 Transcription Factor/genetics , Heart Defects, Congenital/genetics , Mutation , Amino Acid Sequence , Animals , Case-Control Studies , DNA , Exons , Genome, Human , Humans , Molecular Sequence Data , Sequence Alignment
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