RNA-binding protein CELF1 promotes cardiac hypertrophy via interaction with PEBP1 in cardiomyocytes.

Cardiac hypertrophy is considered as a common pathophysiological process in various cardiovascular diseases. CUG triplet repeat-binding protein 1 (CELF1) is an RNA-binding protein that has been shown to be an important post-transcription regulator and involved in several types of cancer, whereas its role in cardiac remodeling remains unclear. Herein, we found that the expression of CELF1 was significantly increased in pressure overload-induced hypertrophic hearts and angiotensin II (Ang II)-induced neonatal cardiomyocytes. Based on transverse aortic constriction-induced cardiac hypertrophy model, CELF1 deficiency markedly ameliorated cardiac hypertrophy, cardiac fibrosis, oxidative stress, and apoptosis. Accordingly, CELF1 deficiency alleviated the production of reactive oxygen species (ROS) and apoptosis of neonatal cardiomyocytes via inhibition of Raf1, TAK1, ERK1/2, and p38 phosphorylation. Mechanistically, depletion or overexpression of CELF1 negatively regulated the protein expression of phosphatidylethanolamine-binding protein 1 (PEBP1), while the mRNA expression of PEBP1 remained unchanged. RNA immunoprecipitation revealed that CELF1 directly interacted with PEBP1 mRNA. Biotin pull-down analysis and dual-luciferase assay showed that CELF1 directly bound to the fragment 1 within 3'UTR of PEBP1. Moreover, knockdown of PEBP1 partially enhanced the production of ROS and apoptosis of neonatal cardiomyocytes inhibited by CELF1 deficiency. In conclusion, CELF1 binds to the 3'UTR of PEBP1 and acts as an endogenous activator of MAPK signaling pathway. Inhibition of CELF1 attenuates pathological cardiac hypertrophy, oxidative stress, and apoptosis, thus could be a potential therapeutic strategy of pathological cardiac hypertrophy.

Effects of percutaneous balloon mitral valvuloplasty in patients with mitral stenosis and atrial fibrillation: a systematic review and meta-analysis.

OBJECTIVE: The study aimed to systematically review the existing literature and assess the effects of percutaneous balloon mitral valvuloplasty (PBMV) in patients with mitral stenosis and atrial fibrillation (AF) as opposed to sinus rhythm (SR). METHODS: Eligible studies were identified from six electronic databases before June 2021. The primary outcome was mitral valve area (MVA), and secondary outcomes were hemodynamic measurements, in-hospital complications, and long-term outcomes. Relative risks (RRs) or weighted mean differences (WMDs) with 95% confidence intervals (CIs) were used as effect sizes. RESULTS: Fifteen studies were included involving 6351 patients. For the primary outcome, the AF group obtained less favourable changes in MVA (WMD: -0.10, 95%CI: -0.14, -0.06) and a significantly smaller postoperative and long-term MVA (WMD: -0.13, 95%CI: -0.18, -0.08 and WMD: -0.10, 95%CI: -0.17, -0.03, respectively) compared to the SR group. For secondary outcome, the AF group was associated with suboptimal outcomes as following (WMD/RR, [95%CI]): higher LAP (1.37, [0.86, 1.87]), more embolism (2.85, [1.44, 5.63]), lower event-free survival (0.89, [0.80, 1.00]), higher incidences of mitral valve replacement (2.20, [1.40, 3.46]), re-PBMV (2.28, [1.63, 3.19]), and mortality (3.28, [2.42, 4.44]). No significant differences were found in other outcomes. CONCLUSIONS: The currently available evidence suggests that PBMV may be less effective in patients with AF than in those with SR. However, early treatment and appropriate management of AF patients undergoing PBMV may benefit the immediate and long-term outcomes.

Human Plasma Transcriptome Implicates Dysregulated S100A12 Expression: A Strong, Early-Stage Prognostic Factor in ST-Segment Elevated Myocardial Infarction: Bioinformatics Analysis and Experimental Verification.

The ability of blood transcriptome analysis to identify dysregulated pathways and outcome-related genes following myocardial infarction remains unknown. Two gene expression datasets (GSE60993 and GSE61144) were downloaded from Gene Expression Omnibus (GEO) Datasets to identify altered plasma transcriptomes in patients with ST-segment elevated myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. GEO2R, Gene Ontology/Kyoto Encyclopedia of Genes and Genomes annotations, protein-protein interaction analysis, etc., were adopted to determine functional roles and regulatory networks of differentially expressed genes (DEGs). Dysregulated expressomes were verified at transcriptional and translational levels by analyzing the GSE49925 dataset and our own samples, respectively. A total of 91 DEGs were identified in the discovery phase, consisting of 15 downregulated genes and 76 upregulated genes. Two hub modules consisting of 12 hub genes were identified. In the verification phase, six of the 12 hub genes exhibited the same variation patterns at the transcriptional level in the GSE49925 dataset. Among them, S100A12 was shown to have the best discriminative performance for predicting in-hospital mortality and to be the only independent predictor of death during follow-up. Validation of 223 samples from our center showed that S100A12 protein level in plasma was significantly lower among patients who survived to discharge, but it was not an independent predictor of survival to discharge or recurrent major adverse cardiovascular events after discharge. In conclusion, the dysregulated expression of plasma S100A12 at the transcriptional level is a robust early prognostic factor in patients with STEMI, while the discrimination power of the protein level in plasma needs to be further verified by large-scale, prospective, international, multicenter studies.

Human Plasma Metabolomics Identify 9-cis-retinoic Acid and Dehydrophytosphingosine Levels as Novel biomarkers for Early Ventricular Fibrillation after ST-elevated Myocardial Infarction.

The relevant metabolite biomarkers for risk prediction of early onset of ventricular fibrillation (VF) after ST-segment elevation myocardial infarction (STEMI) remain unstudied. Here, we aimed to identify these imetabolites and the important metabolic pathways involved, and explore whether these metabolites could be used as predictors for the phenotype. Plasma samples were obtained retrospectively from a propensity-score matched cohort including 42 STEMI patients (21 consecutive VF and 21 non-VF). Ultra-performance liquid chromatography and mass spectrometry in combination with a comprehensive analysis of metabolomic data using Metaboanalyst 5.0 version were performed. As a result, the retinal metabolism pathway proved to be the most discriminative for the VF phenotype. Furthermore, 9-cis-Retinoic acid (9cRA) and dehydrophytosphingosine proved to be the most discriminative biomarkers. Biomarker analysis through receiver operating characteristic (ROC) curve showed the 2-metabolite biomarker panel yielding an area under the curve (AUC) of 0.836. The model based on Monte Carlo cross-validation found that 9cRA had the greatest probability of appearing in the predictive panel of biomarkers in the model. Validation of model efficiency based on an ROC curve showed that the combination model constructed by 9cRA and dehydrophytosphingosine had a good predictive value for early-onset VF after STEMI, and the AUC was 0.884 (95% CI 0.714-1). Conclusively, the retinol metabolism pathway was the most powerful pathway for differentiating the post-STEMI VF phenotype. 9cRA was the most important predictive biomarker of VF, and a plasma biomarker panel made up of two metabolites, may help to build a potent predictive model for VF.

LncRNA Oprm1 overexpression attenuates myocardial ischemia/reperfusion injury by increasing endogenous hydrogen sulfide via Oprm1/miR-30b-5p/CSE axis.

AIMS: Ischemia/reperfusion (I/R) injury largely limits the efficacy of revascularization in acute myocardial infarction. Long noncoding RNA (lncRNA) Oprm1 is protective in cerebral I/R injury. This study aimed to investigate the effect of lncRNA Oprm1 on myocardial I/R injury and its mechanism. MAIN METHODS: We ligated and then released the left anterior descending coronary artery of adult male rats to build the I/R model in vivo. At the same time, an H9c2 cardiomyocytes hypoxia-reoxygenation (H/R) model was also used. Myocardial infarction area, cardiac function, histology, TUNEL staining, cell viability, and vital protein expression was conducted and compared. KEY FINDINGS: LncRNA Oprm1 was significantly down-regulated in the I/R injury model. When administered with the AAV9-Oprm1 vector, the myocardial injury and cardiac function were mitigated and preserved, with apoptosis reduced. The cystathionine-γ-lyase (CSE) expression and hydrogen sulfide (H2S) expression were increased. The dual-luciferase reporter gene revealed the targeted relationship between lncRNA Oprm1 and miR-30b-5p. In H9c2 cardiomyocytes models, the miR-30b-5p blocked the protective effect of lncRNA Oprm1 on H/R injury, when Bcl-2, Bcl-xl was down-regulated, and HIF-1α, Bnip-3, Caspase-3, and Caspase-9 up-regulated. SIGNIFICANCE: LncRNA Oprm1can competitively combines with miR-30b-5p, which down-regulates the expression of CSE. When administered with lncRNA Oprm1, increased endogenous H2S can reduce apoptosis and protect the myocardium from I/R injury via activating PI3K/Akt pathway and inhibiting HIF1-α activity.

Effect of sequential nicorandil on myocardial microcirculation and short-term prognosis in acute myocardial infarction patients undergoing coronary intervention.

BACKGROUND: This study aims to observe the effects of the intracoronary and peripheral venous administration of nicorandil for the postoperative myocardial microcirculation and short-term prognosis of ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PPCI) treatment. METHODS: A total of 140 STEMI patients were divided into three groups according to different patterns of administration: sequential nicorandil group, intracoronary nicorandil group and control group. The main observation indexes included coronary blood flow and myocardial perfusion immediately after PPCI, while the secondary observation indexes included major adverse cardiovascular events (MACE) and left ventricular ejection fraction (LVEF) during the period of hospitalization. RESULTS: After PPCI, the difference in the proportion of patients with thrombolysis in myocardial infarction (TIMI) flow grade 3 among the three groups was statistically significant (P=0.036), where this proportion was higher in the sequential nicorandil group and intracoronary nicorandil group than in the control group (P=0.022 and P=0.047); The difference in corrected TIMI frame count (CTFC) among the three groups was statistically significant (P=0.022), where CTFC was lower in the sequential nicorandil group and intracoronary nicorandil group than in the control group (P=0.010, P=0.031); The differences in the proportion of patients with complete ST resolution (STR) and advancing of enzyme peak time to within 12 h between each two groups were statistically significant (P<0.001), where this proportion was the highest in the sequential nicorandil group; The difference in the CK-MB peak among the three groups was statistically significant (P=0.036), where the CK-MB peak was lower in the sequential nicorandil group than in the control group (P=0.012); The difference in the incidence of MACE between each two groups was statistically significant (P<0.001), where this incidence was the lowest in the sequential nicorandil group; The differences in the proportion of patients with advancing of enzyme peak time to within 14 h and LVEF among the three groups were not statistically significant (P=0.722 and P=0.284). CONCLUSIONS: Compared with intracoronary use alone, the intracoronary and peripheral intravenous use of nicorandil can better improve myocardial microcirculation and short-term prognosis.

Human Plasma Metabolomics Implicates Modified 9-cis-Retinoic Acid in the Phenotype of Left Main Artery Lesions in Acute ST-Segment Elevated Myocardial Infarction.

The detection of left main coronary artery disease (LMCAD) is crucial before ST-segment elevated myocardial infarction (STEMI) or sudden cardiac death. The aim of this study was to identify characteristic metabolite modifications in the LMCAD phenotype, using the metabolomics technique. Metabolic profiles were generated based on ultra-performance liquid chromatography and mass spectrometry, combined with multivariate statistical analysis. Plasma samples were collected prospectively from a propensity-score matched cohort including 44 STEMI patients (22 consecutive LMCAD and 22 non-LMCAD), and 22 healthy controls. A comprehensive metabolomics data analysis was performed with Metaboanalyst 3.0 version. The retinol metabolism pathway was shown to have the strongest discriminative power for the LMCAD phenotype. According to biomarker analysis through receiver-operating characteristic curves, 9-cis-retinoic acid (9cRA) dominated the first page of biomarkers, with area under the curve (AUC) value 0.888. Next highest were a biomarker panel consisting of 9cRA, dehydrophytosphingosine, 1H-Indole-3-carboxaldehyde, and another seven variants of lysophosphatidylcholines, exhibiting the highest AUC (0.933). These novel data propose that the retinol metabolism pathway was the strongest differential pathway for the LMCAD phenotype. 9cRA was the most critical biomarker of LMCAD, and a ten-metabolite plasma biomarker panel, in which 9cRA remained the weightiest, may help develop a potent predictive model for LMCAD in clinic.

[Risk factors for coronary artery disease stimulate urokinase receptor expression on monocytes].

OBJECTIVE: To evaluate the effect of risk factors for coronary artery disease (CAD) on urokinase receptor (uPAR) expression on monocytes. METHODS: A total of 106 patients were enrolled and divided into five risk-factor groups: sixteen with hypertension, twenty-four with dyslipidemia, eighteen with hypertension + obesity, eighteen with dyslipidemia + obesity and thirty with hypertension + dyslipidemia + obesity. Seventeen healthy volunteers were recruited as control group. Monocyte expression of uPAR and mean fluorescence intensity index (MFI Index) of uPAR were measured by flow cytometer (FACSCalibur). RESULTS: No difference in monocyte uPAR expression was detected between hypertension and control group [(4.9 +/- 12.5)% vs. (7.7 +/- 10.3)%, P=0.74]. However, the uPAR expression was raised to (23.7 +/- 22.5)% in hyperlipidemia group, a 3.9- and a 2.1-fold increase compared with those in hypertension (P<0.01) and control group (P<0.05), respectively. When combined with obesity, uPAR expression was elevated further to (32.9 +/- 30.8)% in hypertension + obesity group, (37.4 +/- 31.4)% in dyslipidemia + obesity group and (23.8 +/- 20.5)% in hypertension + dyslipidemia + obesity group, all having statistical significance compared with control group or hypertension group (P<0.01). The results were the same when corrected by age, BMI and hs-CRP. uPAR MFI Index was increased from 0.78 +/- 0.86 in control group to 1.91 +/- 1.97 and 3.33 +/- 2.52 in dyslipidemia group and hypertension + obesity group, respectively, P<0.05. Linear regression analysis revealed a significant correlation between uPAR expression and FBG concentration in dyslipidemia group, r=0.72, P=0.04. CONCLUSIONS: uPAR expression was elevated on monocytes in patients with risk factors for CAD. Dyslipidemia and obesity may contribute to the increase of uPAR expression.

Ischemic Postconditioning Before Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction Reduces Contrast-induced Nephropathy and Improves Long-term Prognosis.

BACKGROUND AND AIMS: Contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) is one of the major adverse outcomes affecting the prognosis of patients with acute ST-segment elevation myocardial infarction (STEMI). Ischemic postconditioning prior to PCI (pre-PCI) in patients with STEMI is hypothesized to be protective against CIN after PCI. METHODS: A total of 251 patients with STEMI were randomized into two groups: ischemic postconditioning group (n = 123, age, 61.1 ± 12.5 years) who underwent ischemic postconditioning prior to PCI; control group (n = 128; age, 64.1 ± 12.1 years) who underwent only PCI. Ischemic postconditioning was administered by three cycles of deflation and inflation of the balloon (1-min ischemia and 1-min reperfusion) starting 1 min after infarct-related artery (IRA) opening. Diagnostic criterion for CIN was: increase in serum creatinine level by ≥0.5 mg/dL or by ≥25% increase from preoperative level within 48 h of surgery. All patients were followed for 1 year for incidence of major cardiovascular events (MACE). RESULTS: The incidence of postoperative CIN in the ischemic postconditioning group was 5.69% as compared to 14.06% in the control group (p <0.05). At one year, the MACE incidence in the ischemic postconditioning group was 7.32% as compared to 15.63% in the control group (p <0.05). CONCLUSIONS: Pre-PCI ischemic postconditioning in STEMI patients significantly reduces the post-PCI incidence of CIN and improves long-term prognosis.