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BACKGROUND: The mechanism of cardiac reverse remodeling (CRR) mediated by the left ventricular assist device remains unclear. This study aims to identify the specific cell type responsible for CRR and develop the therapeutic target that promotes CRR. METHODS: The nuclei were extracted from the left ventricular tissue of 4 normal controls, 4 CRR patients, and 4 no cardiac reverse remodeling patients and then subjected to single-nucleus RNA sequencing for identifying key cell types responsible for CRR. Gene overexpression in transverse aortic constriction and dilated cardiomyopathy heart failure mouse model (C57BL/6J background) and pathological staining were performed to validate the results of single-nucleus RNA sequencing. RESULTS: Ten cell types were identified among 126â 156 nuclei. Cardiomyocytes in CRR patients expressed higher levels of ATP5F1A than the other 2 groups. The macrophages in CRR patients expressed more anti-inflammatory genes and functioned in angiogenesis. Endothelial cells that elevated in no cardiac reverse remodeling patients were involved in the inflammatory response. Echocardiography showed that overexpressing ATP5F1A through cardiomyocyte-specific adeno-associated virus 9 demonstrated an ability to improve heart function and morphology. Pathological staining showed that overexpressing ATP5F1A could reduce fibrosis and cardiomyocyte size in the heart failure mouse model. CONCLUSIONS: The present results of single-nucleus RNA sequencing and heart failure mouse model indicated that ATP5F1A could mediate CRR and supported the development of therapeutics for overexpressing ATP5F1A in promoting CRR.
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Ischemia reperfusion injury (IRI), often related to surgical procedures, is one of the important causes of acute kidney injury (AKI). To decipher the dynamic process of AKI caused by IRI (with prolonged ischemia phase), we performed single-cell RNA sequencing (scRNA-seq) of clinically relevant IRI murine model with different ischemic intervals. We discovered that Slc5a2hi proximal tubular cells were susceptible to AKI and highly expressed neutral amino acid transporter gene Slc6a19, which was dramatically decreased over the time course. With the usage of mass spectrometry-based metabolomic analysis, we detected that the level of neutral amino acid isoleucine dropped off in AKI mouse plasma metabolites. And the reduction of plasma isoleucine was also verified in patients with cardiac surgery-associated acute kidney injury (CSA-AKI). The findings advanced the understanding of dynamic process of AKI and introduced reduction of isoleucine as a potential biomarker for CSA-AKI.
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The vascular endothelial barrier dysfunction is associated with the pathogenesis of many cardiovascular diseases, such as atherosclerosis (AS). This study aims to identify specific antigen (Ag, in short)-specific polymorphonuclear neutrophils (PMN) in AS patients and to investigate the role of "Ag-specific" PMN activation in causing vascular endothelial barrier dysfunction. In this study, PMNs were isolated from blood samples collected from patients with AS and analyzed with immunological approaches. Human umbilical vein endothelial cells (HUVEC) monolayers were used as a vascular endothelial barrier model. The results showed that "Ag-specific" PMNs were identified in the blood of 50 AS patients. This subset of PMN was featured as the FcγRI and specific IgG (sIgG) complexes on the cell surface; exposure to specific Ags triggered the "Ag-specific" PMNs to release proinflammatory cytokines. PMN-derived cytokine levels in the serum were positively correlated with the serum levels of sIgG in AS patients. Exposure of naive PMNs to sIgG formed FcγRI and sIgG complexes on the surface; this conferred PMNs the property to be recognized and activated by specific Ag. Stimulation of "Ag-specific" PMN activated the mitogen-activated protein kinase and the activities of nuclear factor activated T cells and promoted the gene transcription of tumor necrosis factor-α. Coculture of "Ag-specific" PMNs and HUVEC monolayers in the presence of specific Ag resulted in the HUVEC monolayer barrier dysfunction. In conclusion, "Ag-specific" PMNs were identified in AS patients. Activation of the PMNs compromised vascular endothelial barrier function. Therefore, to regulate the "Ag-specific" PMN's activities may have translational potential in the treatment of AS.
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BACKGROUND: Acute kidney injury (AKI) occurs in about 30% of patients with cardiac surgery, but the pathogenesis of cardiac surgery-associated acute kidney injury (CSA-AKI) remains unclear and there are no predictive biomarkers or diagnostic criteria specific for CSA-AKI beyond the general clinical variables for AKI like serum creatinine (SCr). METHODS AND RESULTS: We measured the plasma levels of 48 cytokines within 24 h after cardiac surgery in a total of 306 adult patients including 204 with and 102 without AKI, and then evaluated the diagnostic efficacy of these cytokines for the development of CSA-AKI via ANOVA and Pearson correlation analysis. Among these 48 cytokines, 20 of them were significantly different in the AKI patients compared with the non-AKI patients. In particularly, 13 cytokines displayed tremendous changes with the P < 1E-5. Moreover, 10 of the 48 cytokines in the plasma were significantly different among the patients with different stages of AKI. Specifically, 6 cytokines exhibited immense differences with the P < 1E-5. Additionally, 7 of the 48 cytokines have the correlation coefficient of r > 0.5 with the postoperative changes of SCr after cardiac surgery. CONCLUSION: Taken all the results together, IFN-γ and SCGF-ß were the most relevant two cytokines that were not only remarkably changed in adult CSA-AKI patients during the first 24 h after cardiac surgery, but also significantly correlated with the postoperative changes of SCr after cardiac surgery. Therefore, IFN-γ and SCGF-ß might be novel predictive plasma biomarker, as well as potential therapeutic targets specific for adult CSA-AKI.