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BACKGROUND: Angiogenesis, which plays a critical role in embryonic development and tissue repair, is controlled by a set of angiogenic signaling pathways. As a TF (transcription factor) belonging to the basic helix-loop-helix family, HEY (hairy/enhancer of split related with YRPW motif)-1 (YRPW motif, abbreviation of 4 highly conserved amino acids in the motif) has been identified as a key player in developmental angiogenesis. However, the precise mechanisms underlying HEY1's actions in angiogenesis remain largely unknown. Our previous studies have suggested a potential role for posttranslational SUMOylation in the dynamic regulation of vascular development and organization. METHODS: Immunoprecipitation, mass spectrometry, and bioinformatics analysis were used to determine the biochemical characteristics of HEY1 SUMOylation. The promoter-binding capability of HEY1 was determined by chromatin immunoprecipitation, dual luciferase, and electrophoretic mobility shift assays. The dimerization pattern of HEY1 was determined by coimmunoprecipitation. The angiogenic capabilities of endothelial cells were assessed by CCK-8 (cell counting kit-8), 5-ethynyl-2-deoxyuridine staining, wound healing, transwell, and sprouting assays. Embryonic and postnatal vascular growth in mouse tissues, matrigel plug assay, cutaneous wound healing model, oxygen-induced retinopathy model, and tumor angiogenesis model were used to investigate the angiogenesis in vivo. RESULTS: We identified intrinsic endothelial HEY1 SUMOylation at conserved lysines by TRIM28 (tripartite motif containing 28) as the unique E3 ligase. Functionally, SUMOylation facilitated HEY1-mediated suppression of angiogenic RTK (receptor tyrosine kinase) signaling and angiogenesis in primary human endothelial cells and mice with endothelial cell-specific expression of wild-type HEY1 or a SUMOylation-deficient HEY1 mutant. Mechanistically, SUMOylation facilitates HEY1 homodimer formation, which in turn preserves HEY1's DNA-binding capability via recognition of E-box promoter elements. Therefore, SUMOylation maintains HEY1's function as a repressive TF controlling numerous angiogenic genes, including RTKs and Notch pathway components. Proangiogenic stimuli induce HEY1 deSUMOylation, leading to heterodimerization of HEY1 with HES (hairy and enhancer of split)-1, which results in ineffective DNA binding and loss of HEY1's angiogenesis-suppressive activity. CONCLUSIONS: Our findings demonstrate that reversible HEY1 SUMOylation is a molecular mechanism that coordinates endothelial angiogenic signaling and angiogenesis, both in physiological and pathological milieus, by fine-tuning the transcriptional activity of HEY1. Specifically, SUMOylation facilitates the formation of the HEY1 transcriptional complex and enhances its DNA-binding capability in endothelial cells.
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Células Endoteliales , Sumoilación , Animales , Humanos , Ratones , Angiogénesis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , ADN/metabolismo , Células Endoteliales/metabolismoRESUMEN
OBJECTIVES: To investigate the prognostic impact and pathophysiological characteristics of fragmented QRS complex (fQRS) on patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). METHODS: This was a multicentre retrospective study recruiting 141 patients with CTD-PAH diagnosed by right heart catheterization (114 cases in the discovery cohort and 27 cases in the validation cohort). fQRS and ST-T change were detected on conventional 12-lead electrocardiogram (ECG). Patients were followed up every 3 months to update their status and the primary end point was all-cause death. Clinical information and ECG characteristics were compared between survival and death groups and Kaplan-Meier curve was used for survival analysis. RESULTS: There were significant differences in age, gender, 6-min walk distance, NT-proBNP, WHO class, presence of fQRS and presence of ST-T change in inferior leads between survival group and death group. Inferior fQRS and ST-T change were significantly associated with right ventricular (RV) dilatation and reduced RV ejection fraction (RVEF). Kaplan-Meier curve showed that all-cause mortality was higher in CTD-PAH with fQRS (p= 0.003) and inferior ST-T change (p= 0.012). Low- and intermediate-risk CTD-PAH with inferior ST-T change had higher all-cause mortality (p= 0.005). The prognostic value of fQRS and inferior ST-T change was validated in external validation cohort. CONCLUSION: The presence of inferior fQRS and ST-T change could predict poor prognosis in CTD-PAH. CLINICAL TRIAL REGISTRATION NUMBER: NCT05980728, https://clinicaltrials.gov.
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INTRODUCTION: The Agatston coronary artery calcification score (CACS) is an assessment index for coronary artery calcification (CAC). This study aims to explore the characteristics of CAC in end-stage kidney disease (ESKD) patients and establish a predictive model to assess the risk of severe CAC in patients. METHODS: CACS of ESKD patients was assessed using an electrocardiogram-gated coronary computed tomography (CT) scan with the Agatston scoring method. A predictive nomogram model was established based on stepwise regression. An independent validation cohort comprised of patients with ESKD from multicentres. RESULTS: 369 ESKD patients were enrolled in the training set, and 127 patients were included in the validation set. In the training set, the patients were divided into three subgroups: no calcification (CACS = 0, n = 98), mild calcification (0 < CACS ≤ 400, n = 141) and severe calcification (CACS > 400, n = 130). Among the four coronary branches, the left anterior descending branch (LAD) accounted for the highest proportion of calcification. Stepwise regression analysis showed that age, dialysis vintage, ß-receptor blocker, calcium-phosphorus product (Ca × P), and alkaline phosphatase (ALP) level were independent risk factors for severe CAC. A nomogram that predicts the risk of severe CAC in ESKD patients has been internally and externally validated, demonstrating high sensitivity and specificity. CONCLUSION: CAC is both prevalent and severe in ESKD patients. In the four branches of the coronary arteries, LAD calcification is the most common. Our validated nomogram model, based on clinical risk factors, can help predict the risk of severe coronary calcification in ESKD patients who cannot undergo coronary CT analysis.
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Enfermedad de la Arteria Coronaria , Fallo Renal Crónico , Nomogramas , Calcificación Vascular , Humanos , Masculino , Femenino , Fallo Renal Crónico/complicaciones , Persona de Mediana Edad , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/complicaciones , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/complicaciones , Anciano , Factores de Riesgo , Índice de Severidad de la Enfermedad , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/patología , Tomografía Computarizada por Rayos X , Adulto , Medición de RiesgoRESUMEN
Angiogenesis is involved in development, reproduction, wound healing, homeostasis, and other pathophysiological events. Imbalanced angiogenesis predisposes patients to various pathological processes, such as angiocardiopathy, inflammation, and tumorigenesis. MicroRNAs (miRNAs) have been found to be important in regulating cellular processing and physiological events including angiogenesis. However, the role of miRNAs that regulate angiogenesis (angiomiRs) is not fully understood. Here, we observed a downregulation of the miR-196 family in endothelial cells upon hypoxia. Functionally, miR-196b-5p inhibited the angiogenic functions of endothelial cells in vitro and suppressed angiogenesis in Matrigel plugs and skin wound healing in vivo. Mechanistically, miR-196b-5p bound onto the 3' untranslated region (UTR) of high-mobility group AT-hook 2 (HMGA2) mRNA and repressed the translation of HMGA2, which in turn represses HIF1α accumulation in endothelial cells upon hypoxia. Together, our results establish the role of endothelial miR-196b-5p as an angiomiR that negatively regulates endothelial growth in angiogenesis via the hypoxia/miR-196b-5p/HMGA2/HIF1α loop. miR-196b-5p and its regulatory loop could be an important addition to the molecular mechanisms underlying angiogenesis and may serve as potential targets for antiangiogenic therapy.
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Células Endoteliales , Hipoxia , MicroARNs , Humanos , Línea Celular Tumoral , Proliferación Celular , Regulación hacia Abajo , Células Endoteliales/metabolismo , Hipoxia/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neovascularización Patológica/metabolismoRESUMEN
AIMS: Our objective was to explore whether the accuracy of the transitional zone index (TZI) for outflow tract ventricular arrhythmias (OT-VAs) origin is affected by cardiac rotation and the additive value of interventricular septum angle (IVSa) obtained from coronary computed tomography angiography (CCTA). METHODS: Standard 12-lead ECGs of OT-VAs with inferior axis in consecutive patients undergoing both CCTA examination and successful ablation were retrospectively analyzed. The IVSa was defined as an angle between the long axis of IVS and sagittal axis of the body from CCTA. RESULTS: 64 patients (31 men; mean age 54.2 ± 11.6 years) were enrolled. The OT-VAs exhibited right ventricular outflow tract origin in 46 (71.9%) patients and 36 (78.3%) were diagnosed correctly by TZI. The left ventricular outflow tract origin OT-VAs was observed in 18 (28.1%) patients and 16 (88.9%) were diagnosed correctly by TZI. The patients were then divided into TZI correct group (n = 52) and TZI incorrect group (n = 12). In the TZI incorrect group, 11/12 (91.7%) cases were R/S transition in lead V3 with the TZ score during premature ventricular contractions [2.8(2.5-3.4)], and the TZI between -1.5 and 0. The IVSa was significantly larger in the TZI incorrect group than correct group (52.0 ± 6.9° vs. 39.0 ± 6.1°; p < .0001). The IVSa ≥46° predicted TZI incorrect with 92% sensitivity, 94% specificity, and 94% accuracy. CONCLUSION: The IVSa is a novel cardiac rotation index that reliably improves TZI to differentiate the OT-VAs origin, especially for the OT-VAs with lead V3 R/S transition.