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1.
Mol Med ; 28(1): 158, 2022 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-36536281

RESUMO

BACKGROUND: Acute thoracic aortic dissection (ATAD) is a fatal condition characterized by tear of intima, formation of false lumen and rupture of aorta. However, the subpopulations of normal and dissected aorta remain less studied. METHODS: Single-cell RNA sequencing was performed including 5 patients with ATAD and 4 healthy controls. Immunohistochemistry and immunofluorescence were used to verify the findings. RESULTS: We got 8 cell types from human ascending aorta and identified 50 subpopulations including vascular smooth muscle cells (VSMCs), endothelial cells, fibroblasts, neutrophils, monocytes and macrophages. Six transmembrane epithelial antigen of prostate 4 metalloreductase (STEAP4) was identified as a new marker of synthetic VSMCs. CytoTRACE identified subpopulations with higher differentiation potential in specified cell types including synthetic VSMCs, enolase 1+ fibroblasts and myeloid-derived neutrophils. Synthetic VSMCs-derived C-X-C motif chemokine ligand 12 (CXCL12) might interact with neutrophils and fibroblasts via C-X-C motif chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3), respectively, which might recruit neutrophils and induce transdifferentitation of fibroblasts into synthetic VSMCs. CONCLUSION: We characterized signatures of different cell types in normal and dissected human ascending aorta and identified a new marker for isolation of synthetic VSMCs. Moreover, we proposed a potential mechanism that synthetic VSMCs might interact with neutrophils and fibroblasts via CXCL12-CXCR4/ACKR3 axis whereby deteriorating the progression of ATAD, which might provide new insights to better understand the development and progression of ATAD.


Assuntos
Aorta Torácica , Dissecção Aórtica , Masculino , Humanos , Células Endoteliais , Transcriptoma , Aorta , Fenótipo
2.
Am J Physiol Lung Cell Mol Physiol ; 317(5): L615-L624, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31461311

RESUMO

Nur77 is an orphan nuclear receptor implicated in the regulation of a wide range of biological processes, including the maintenance of systemic blood vessel homeostasis. Although Nur77 is known to be expressed in the lung, its role in regulating pulmonary vascular functions remains entirely unknown. In this study, we found that Nur77 is expressed at high levels in the lung, and its expression is markedly upregulated in response to LPS administration. While the pulmonary vasculature of mice that lacked Nur77 appeared to function normally under homeostatic conditions, we observed a dramatic decrease in its barrier functions after exposure to LPS, as demonstrated by an increase in serum proteins in the bronchoalveolar lavage fluid and a reduction in the expression of endothelial junctional proteins, such as vascular endothelial cadherin (VE-cadherin) and ß-catenin. Similarly, we found that siRNA knockdown of Nur77 in lung microvascular endothelial cells also reduced VE-cadherin and ß-catenin expression and increased the quantity of fluorescein isothiocyanate-labeled dextran transporting across LPS-injured endothelial monolayers. Consistent with Nur77 playing a vascular protective role, we found that adenoviral-mediated overexpression of Nur77 both enhanced expression of VE-cadherin and ß-catenin and augmented endothelial barrier protection to LPS in cultured cells. Mechanistically, Nur77 appeared to mediate its protective effects, at least in part, by binding to ß-catenin and preventing its degradation. Our findings demonstrate a key role for Nur77 in the maintenance of lung endothelial barrier protection to LPS and suggest that therapeutic strategies aimed at augmenting Nur77 levels might be effective in treating a wide variety of inflammatory vascular diseases of the lung.


Assuntos
Lesão Pulmonar Aguda/complicações , Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Lipopolissacarídeos/efeitos adversos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/fisiologia , Pneumonia/prevenção & controle , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Camundongos , Camundongos Knockout , Pneumonia/etiologia , Pneumonia/patologia
3.
Heart Surg Forum ; 22(6): E486-E493, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31895035

RESUMO

BACKGROUND: To compare baseline and outcome characteristics of multiple valve surgery with single-valve procedures in a multicenter patient population of mainland China. METHODS: From January 2008 to December 2012, data from 14,322 consecutive patients older than 16 years who underwent heart valve surgery at five cardiac surgical centers (except pulmonary valve operations) were collected. The patients were divided into seven subgroups according to the type of valve procedures, and baseline characteristics and postoperative outcomes were contrasted between all seven combinations of single-valve and multiple-valve procedures involving aortic, mitral, and tricuspid valves. Two independent logistic regression analyses were performed and multivariable risk factors for mortality were compared, with emphasis on single-valve versus multiple-valve surgery. RESULTS: Baseline characteristics for MUV procedures (n = 8945) shared many differences to those for single-valve procedures (n = 5377). Proportion of females, chronic obstructive pulmonary disease, cerebrovascular disease, renal impairment, congestive heart failure, NHYA class III-IV, atrial fibrillation, pulmonary hypertension, and decreased ejection fraction were more common in MUV subgroups, and smoker, hypertension, dyslipidemia, active infectious endocarditis, and coronary bypass graft was less frequent. In-hospital mortality was higher for MUV as compared with single-valve procedures (2.4% versus 1.6%, P = .007). Preoperative independent predictors for mortality of patients undergoing MUV procedures were age, chronic obstructive pulmonary disease, diabetes mellitus, renal dysfunction, dialysis, congestive heart failure, cardiogenic shock, NYHA class III-IV, mitral stenosis, tricuspid regurgitation, mitral valve replacement, and concomitant CABG. However, risk factors for mortality were relatively different between single-valve and MUV procedures. CONCLUSION: Baseline characteristics and epidemiology were different between MUV and single-valve procedures. The in-hospital mortality and postoperative complications for MUV procedures remained considerably higher and determinants of mortality were relatively different across procedures types. These findings serve as a benchmark for further studies, as well as suggest a continued search for explanations of MUV outcomes.


Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Doenças das Valvas Cardíacas/cirurgia , Valvas Cardíacas/cirurgia , Idoso , Procedimentos Cirúrgicos Cardíacos/métodos , China , Feminino , Implante de Prótese de Valva Cardíaca/efeitos adversos , Implante de Prótese de Valva Cardíaca/métodos , Mortalidade Hospitalar , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Reoperação , Estudos Retrospectivos , Fatores de Risco
4.
Cell Biol Int ; 41(10): 1076-1082, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28653781

RESUMO

Autophagy is a ubiquitous intracellular process for cellular homeostasis maintenance by recycling damaged protein and organelles. Dysregulation of cardiomyocytes autophagic activity is implicated in various heart diseases. Recent studies had demonstrated that long non-coding RNAs (lncRNAs) played crucial roles on modulation of autophagic activity. In this study, we first established an angiotensin II-induced autophagy model on neonatal rat cardiomyocytes. Western blot assay confirmed that the expression of Beclin 1 and the conversion of soluble LC3-I to lipid bound LC3-II were significantly increased at 12 h after angiotensin II stimulation, but the cardiomyocytes surface area and hypertrophic markers expression had no significant change. Then microarray analysis and real-time PCR were applied to detect differentially expressed lncRNAs during cardiomyocytes autophagy. A total of 1,249 lncRNAs were determined as differentially expressed, including 700 upregulated lncRNAs and 549 downregulated lncRNAs. LncRNAs subgroup analysis showed there were 43 transcribed ultra-conserved noncoding RNAs (T-UCRs) differentially expressed in cardiomyocytes autophagy, of which 26 T-UCRs were upregulated and 17 T-UCRs were downregulated. Bioinformatics analysis further showed that 94 differentially expressed lncRNAs contained potential binding sites of miR-22, a pro-hypertrophic and pro-autophagic microRNA. Therefore, these differentially expressed lncRNAs might play critical roles in cardiomyocytes autophagy. This finding would provide an experimental basis for future investigation on ischemic heart disease.


Assuntos
Angiotensina II/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , RNA Longo não Codificante/genética , Angiotensina II/genética , Animais , Autofagia/genética , Biologia Computacional , Perfilação da Expressão Gênica , MicroRNAs/genética , MicroRNAs/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Transcriptoma
5.
Arterioscler Thromb Vasc Biol ; 36(2): 361-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26634653

RESUMO

OBJECTIVE: Thrombomodulin is highly expressed on the lumenal surface of vascular endothelial cells (ECs) and possesses potent anticoagulant, antifibrinolytic, and anti-inflammatory activities in the vessel wall. However, the regulation of thrombomodulin expression in ECs remains largely unknown. APPROACHES AND RESULTS: In this study, we characterized nuclear receptor 4A family as a novel regulator of thrombomodulin expression in vascular ECs. We demonstrated that both nuclear receptors 4A, Nur77 and Nor1, robustly increase thrombomodulin mRNA and protein levels in human vascular ECs and in mouse liver tissues after adenovirus-mediated transduction of Nur77 and Nor1 cDNAs. Moreover, Nur77 deficiency and knockdown of Nur77 and Nor1 expression markedly attenuated the basal and vascular endothelial growth factor165-stimulated thrombomodulin expression. Mechanistically, we found that Nur77 and Nor1 increase thrombomodulin expression by acting through 2 different mechanisms. We showed that Nur77 barely affects thrombomodulin promoter activity, but significantly increases thrombomodulin mRNA stability, whereas Nor1 enhances thrombomodulin expression mainly through induction of Kruppel-like factors 2 and 4 in vascular ECs. Furthermore, we demonstrated that both Nur77 and Nor1 significantly increase protein C activity and inhibit tumor necrosis factor α-induced prothrombotic effects in human ECs. Deficiency of Nur77 increases susceptibility to arterial thrombosis, whereas enhanced expression of Nur77 and Nor1 protects mice from arterial thrombus formation. CONCLUSIONS: Our results identified nuclear receptors 4A as novel regulators of thrombomodulin expression and function in vascular ECs and provided a proof-of-concept demonstration that targeted increasing expression of Nur77 and Nor1 in the vascular endothelium might represent a novel therapeutic approach for the treatment of thrombotic disorders.


Assuntos
Estenose das Carótidas/prevenção & controle , Proteínas de Ligação a DNA/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Trombomodulina/metabolismo , Trombose/prevenção & controle , Animais , Coagulação Sanguínea , Estenose das Carótidas/genética , Estenose das Carótidas/metabolismo , Células Cultivadas , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Humanos , Masculino , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Regiões Promotoras Genéticas , Proteína C/metabolismo , Interferência de RNA , Estabilidade de RNA , RNA Mensageiro/metabolismo , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Transdução de Sinais , Trombomodulina/genética , Trombose/genética , Trombose/metabolismo , Fatores de Tempo , Transdução Genética , Transfecção , Regulação para Cima
6.
Biochem Biophys Res Commun ; 479(2): 358-364, 2016 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-27644881

RESUMO

The aortic medial degeneration is the key histopathologic feature of Thoracic aortic dissection (TAD). The aim of this study was to identify the change of autophagic activity in the aortic wall during TAD development, and to explore the roles of autophagy on regulating functional properties of smooth muscle cells (SMCs). Firstly, compared with control group (n = 11), the increased expression of autophagic markers Beclin1 and LC3 was detected in the aortic wall from TAD group (n = 23) by immunochemistry and western blot. We found that more autophagic vacuoles were present in the aortic wall of TAD patients using Transmission electron microscopy. Next, autophagic activity was examined in AD mice model established by ß-aminopropionitrile fumarate (BAPN) and angiotensin II. Immunochemistry proved that autophagic activity was dynamically changed during AD development. Beclin1 and LC3 were detected up-regulated in the aortic wall in the second week after BAPN feeding, earlier than the fragmentation or loss of elastic fibers. When AD occurred in the 4th week, the expression of Beclin1 and LC3 began to decrease, but still higher than the control. Furthermore, autophagy was found to inhibit starvation-induced apoptosis of SMCs. Meanwhile, blockage of autophagy could suppress PDGF-induced phenotypic switch of SMCs. Taken together, autophagic activity was dynamically changed in the aortic wall during TAD development. The abnormal autophagy could regulate the functional properties of aortic SMCs, which might be the potential pathogenesis of TAD.


Assuntos
Aorta Torácica/patologia , Dissecção Aórtica/patologia , Autofagia , Miócitos de Músculo Liso/metabolismo , Aminopropionitrilo/análogos & derivados , Aminopropionitrilo/química , Angiotensina II/química , Animais , Aorta Torácica/metabolismo , Apoptose , Proteína Beclina-1/metabolismo , Diferenciação Celular , Proliferação de Células , Elasticidade , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Proteínas Associadas aos Microtúbulos/metabolismo , Fenótipo , Regulação para Cima
7.
Arterioscler Thromb Vasc Biol ; 35(10): 2153-60, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26293469

RESUMO

OBJECTIVE: Endothelial nitric oxide synthase (eNOS) is an important regulator of vascular function and its expression is regulated at post-transcriptional levels through a yet unknown mechanism. The purpose of this study is to elucidate the post-transcriptional factors regulating eNOS expression and function in endothelium. APPROACHES AND RESULTS: To elucidate the molecular basis of tumor necrosis factor (TNF)-α-mediated eNOS mRNA instability, biotinylated eNOS 3'-untranslational region (UTR) was used to purify its associated proteins by RNA affinity chromatography from cytosolic fractions of TNF-α-stimulated human umbilical vein endothelial cells (HUVECs). We identified 2 cytosolic proteins, with molecular weight of 52 and 57 kDa, which specifically bind to eNOS 3'-UTR in response to TNF-α stimulation. Matrix-assisted laser desorption ionization time-of-flight mass spectrometric analysis identified the 57-kDa protein as polypyrimidine tract-binding protein 1 (PTB1). RNA gel mobility shift and UV cross-linking assays demonstrated that PTB1 binds to a UCUU-rich sequence in eNOS 3'-UTR, and the C-terminal half of PTB1 is critical to this interaction. Importantly, PTB1 overexpression leads to decreased activity of luciferase gene fused with eNOS 3'-UTR as well as reduced eNOS expression and activity in human ECs. In HUVECs, we show that TNF-α markedly increased PTB1 expression, whereas adenovirus-mediated PTB1 overexpression decreased eNOS mRNA stability and reduced protein expression and endothelium-dependent relaxation. Furthermore, knockdown of PTB1 substantially attenuated TNF-α-induced destabilization of eNOS transcript and downregulation of eNOS expression. CONCLUSIONS: These results indicate that PTB1 is essential for regulating eNOS expression at post-transcriptional levels and suggest a novel therapeutic target for treatment of vascular diseases associated with inflammatory endothelial dysfunction.


Assuntos
Regulação da Expressão Gênica , Óxido Nítrico Sintase Tipo III/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Células Cultivadas , Regulação para Baixo , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Ligação Proteica , Estabilidade de RNA/genética , RNA Mensageiro/metabolismo , Sensibilidade e Especificidade , Fatores de Transcrição/metabolismo
8.
Heart Lung Circ ; 22(8): 606-11, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23375874

RESUMO

BACKGROUND: To assess the performance of the The European System for Cardiac Operative. Risk Evaluation II (EuroSCORE II) in Chinese patients undergoing heart valve surgery at our centre. METHODS: From January 2006 to December 2011, 3479 consecutive patients who underwent heart valve surgery at our centre were collected and scored according to the original EuroSCORE and EuroSCORE II models. All patients were divided into single valve surgery and multiple valve surgery subgroups. The entire cohort and each subgroup were analysed. Calibration of the original EuroSCORE and EuroSCORE II models was assessed by the Hosmer-Lemeshow (H-L) test. Discrimination was tested by calculating the area under the receiver operating characteristic (ROC) curve. RESULTS: Observed mortality was 3.32% overall, compared to expected mortality 3.84% for the original additive EuroSCORE (H-L: P = 0.013), 3.33% for the original logistic EuroSCORE (H-L: P = 0.08), and 2.52% for the EuroSCORE II (H-L: P < 0.0001). The EuroSCORE II model showed good calibration in predicting in-hospital mortality for patients undergoing single valve surgery (H-L: P = 0.103) and poor calibration for patients undergoing multiple valve surgery (H-L: P < 0.0001). The discriminative power of the original EuroSCORE model (area under the ROC curve of 0.684 and 0.673 for the additive and logistic model, respectively) and EuroSCORE II model (area under the ROC curve of 0.685) for the entire cohort was poor. The discriminative power of the EuroSCORE II model was good for the single valve surgery group (area under the ROC curve of 0.792) and was poor for the multiple valve surgery group (area under the ROC curve of 0.605). CONCLUSION: The EuroSCORE II model gives an accurate prediction for individual operative risk in patients undergoing single valve surgery but an imprecise prediction in patients undergoing multiple valve surgery at our centre. Therefore, the use of the EuroSCORE II model for risk evaluation may be suitable in patients undergoing single valve surgery, and the creation of a new model which accurately predicts outcomes in patients undergoing multiple valve surgery is possibly required at our centre in the future.


Assuntos
Povo Asiático , Procedimentos Cirúrgicos Cardíacos/mortalidade , Mortalidade Hospitalar , Modelos Biológicos , Curva ROC , Adulto , Idoso , Procedimentos Cirúrgicos Cardíacos/métodos , China , Feminino , Doenças das Valvas Cardíacas/mortalidade , Doenças das Valvas Cardíacas/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
9.
J Cardiothorac Surg ; 18(1): 154, 2023 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-37069699

RESUMO

OBJECTIVE: To evaluate the effect of preoperative pulmonary artery pressure on perioperative outcome of end-stage heart failure patients undergoing heart transplantation. METHODS: Retrospective analysis was undertaken on the clinical data of patients receiving heart transplantation in the Department of Cardiovascular Surgery of our hospital from March 2017 to March 2022. A ROC curve analysis was developed between mean pulmonary artery pressure (mPAP) and postoperative mortality using mPAP as diagnostic criteria. Patients were divided into groups based on this threshold to determine the best mPAP threshold value for predicting postoperative nosocomial mortality, and the differences in preoperative and intraoperative data, postoperative complications, and clinical prognosis of patients in the two groups were compared. Patients were followed up to draw the survival curve of patients in the two groups. RESULTS: The study enlisted the participation of 105 patients. ROC curve research revealed that preoperative pulmonary artery pressure was substantially linked with death following heart transplantation, with mPAP = 30.5mmHg being the best threshold. The group with mPAP ≥ 30.5mmHg had a greater incidence of postoperative ECMO support (28.2% vs. 10.6%, P = 0.021) and a higher incidence of in-hospital mortality (15.4% vs. 1.5%, P = 0.019) than the group with mPAP < 30.5mmHg. The postoperative survival rates of 105 patients were 91.3%, 88.7%, 81.6%, and 77.5% at 1, 2, 3, and 4 years, respectively, however, there was no significant difference between the two groups of patients in the postoperative intermediate-far survival rate (P = 0.431). CONCLUSIONS: Preoperative pulmonary artery pressure in patients with end-stage heart failure is intimately correlated with perioperative prognosis of heart transplant recipients. The optimal cut-off mPAP value in predicting perioperative prognosis of heart transplant recipients is 30.5mmHg. In the high mPAP group, perioperative ECMO support rate and perioperative mortality rate are high, which do not affect the medium and long-term prognosis of the recipients undergoing heart transplantation.


Assuntos
Insuficiência Cardíaca , Transplante de Coração , Hipertensão Pulmonar , Humanos , Hipertensão Pulmonar/complicações , Estudos Retrospectivos , Artéria Pulmonar , Prognóstico , Insuficiência Cardíaca/cirurgia , Insuficiência Cardíaca/complicações
10.
Heart Lung Circ ; 21(12): 782-6, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22883627

RESUMO

We sought to explore the pulmonary haemodynamic changes in rheumatic mitral stenosis patients with secondary pulmonary hypertension. The pulmonary artery resistance and compliance of 35 patients with rheumatic mitral stenosis and 12 controls without cardiopulmonary vascular disease were evaluated by using an improved method, which is based on making calculations with parameters obtained from right heart catheterisation. The results are as follows: (1) pulmonary artery compliance in patients with secondary pulmonary hypertension was significantly lower than that of the control group (P<0.01); (2) linear correlation analyses showed that preoperative mean pulmonary artery pressure (mPAP) closely correlated with zero-pressure compliance in the mitral stenosis group (r=-0.745, P<0.05); (3) PAP and pulmonary vascular resistance decreased significantly in both groups with mitral stenosis after infusing 0.5 µg kg(-1) min(-1) of sodium nitroprusside (P<0.01). The pulmonary zero pressure compliance and mean pressure compliance increased significantly in the group with mild pulmonary hypertension; whereas in the severe group, the mean compliance changed with significance as the mPAP decreased (1.51 ± 0.59 vs 1.81 ± 0.77 ml/mmHg), however no significant change occurred in the pulmonary zero pressure compliance (2.35 ± 1.24 ml/mmHg vs. 2.24 ± 1.53 ml/mmHg, P>0.05) The walls of pulmonary artery vessels in patients with pulmonary hypertension secondary to rheumatic mitral stenosis appeared to be remodelled by varying degrees as indicated by their haemodynamic properties. Structural remodelling may be a factor affecting preoperative pulmonary artery pressure. Mitral stenosis patients with severe pulmonary hypertension have significantly lower responses to sodium nitroprusside possibly due to aggradation and deposition of collagen in the artery walls, decreasing constriction and dilation, or atrophy of smooth muscle cells.


Assuntos
Hemodinâmica , Hipertensão Pulmonar/fisiopatologia , Estenose da Valva Mitral/complicações , Artéria Pulmonar/fisiopatologia , Adulto , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Estudos de Casos e Controles , Complacência (Medida de Distensibilidade)/efeitos dos fármacos , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/etiologia , Masculino , Pessoa de Meia-Idade , Nitroprussiato/farmacologia , Resistência Vascular/efeitos dos fármacos
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