Mesenchymal Stem Cell-Derived Exosomal Noncoding RNAs as Alternative Treatments for Myocardial Ischemia-Reperfusion Injury: Current Status and Future Perspectives.

Ischemic cardiomyopathy is treated mainly with thrombolytic drugs, percutaneous coronary intervention, and coronary artery bypass grafting to recanalize blocked vessels. Myocardial ischemia-reperfusion injury (MIRI) is an unavoidable complication of obstructive revascularization. Compared with those of myocardial ischemic injury, few effective therapeutic options are available for MIRI treatment. The pathophysiological mechanisms of MIRI involve the inflammatory response, the immune response, oxidative stress, apoptosis, intracellular Ca2+ overload, and cardiomyocyte energy metabolism. These mechanisms exacerbate MIRI. Mesenchymal stem cell-derived exosomes (MSC-EXOs) can alleviate MIRI through these mechanisms and, to some extent, prevent the limitations caused by direct MSC administration. Therefore, using MSC-EXOs instead of MSCs to treat MIRI is a potentially beneficial cell-free treatment strategy. In this review, we describe the mechanism of action of MSC-EXO-derived noncoding RNAs in the treatment of MIRI and discuss the advantages and limitations of this strategy, as well as possible future research directions.

A Nomogram model for predicting the occurrence of no-reflow phenomenon after percutaneous coronary intervention using the lncRNA TUG1/miR-30e/NPPB biomarkers.

Background: Studies have shown that percutaneous coronary intervention (PCI) is considered as the essential therapeutic strategy for the patients with ST-segment elevation myocardial infarction (STEMI). However; no-reflow could still occur in a few patients after PCI. Studies have reported that biomarkers related to no-reflow pathogenetic components could play a prognostic role in the prediction phenomenon. Hence, this study explored the establishment of nomogram model for predicting the occurrence of no-reflow phenomenon after PCI using the lncRNA TUG1/miR-30e/NPPB biomarkers in patients with STEMI after PCI. Methods: In this observational study, a total of 76 STEMI patients who underwent emergency PCI between January 2018 and December 2021were included. The patients after PCI, were divided into reflow (n=44) and no-reflow groups (n=32). The demographic, environmental and clinical risk factors were assessed and analysed between the groups. Quantitative RT-PCR was used to detect TUG1, miR-30e, and NPPB messenger RNA (mRNA) expression levels in the plasma of patients after PCI. Bioinformatic methods were used to predict the interaction of the plasma TUG1/miR-30e/NPPB axis. The risk factors in the no-reflow group were screened using a logistic-regression analysis, and a nomogram prediction model was constructed and validated. Subsequently, a gene set enrichment analysis revealed the function of lncRNA TUG1. Results: Plasma lncRNA TUG1 and NPPB were more highly expressed and miR-30e was more lowly expressed in the no-reflow group than the normal-reflow group (P<0.001). A negative correlation was observed between lncRNA TUG1 and miR-30e, and between miR-30e and NPPB. However, a positive correlation was observed between lncRNA TUG1 and NPPB mRNA. The bioinformatics analysis predicted multiple binding sites on the lncRNA TUG1 and miR-30e. LncRNA TUG1 [odds ratio (OR): 0.163, 95% confidence interval (CI): 0.021-0.944] and hs-CRP (OR: 2.151, 95% CI: 1.536-3.974) found to be as independent predictors. The C-index of this prediction model was 0.982 (95% CI: 0.956-1.000). Conclusions: TUG1 could function as an effective biomarker for no-reflow among patients with STEMI after PCT and the proposed nomogram may provide information for individualized treatment in patients with STEMI.

Dapagliflozin in Patients with Chronic Heart Failure: A Systematic Review and Meta-Analysis.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors represent newly developed oral antidiabetic drugs that are practiced for type 2 diabetes mellitus management and may decrease the risk of the first hospitalization in heart failure. The activity of SGLT2 inhibitors is not related to glucose, and the effectiveness and safety of SGLT2 inhibitors in individuals with chronic heart failure (CHF) remain unclear. We systematically retrieved PubMed, Cochrane Library, Embase, NCKI, VIP, Wanfang Data, and ClinicalTrials.gov records to identify eligible trials. The primary endpoints were cardiovascular death/hospitalization for heart failure (CV death/HHF), cardiovascular death, and hospitalization for heart failure. Secondary endpoints included hypoglycemia, volume depletion, urinary tract infection, left ventricular ejection fraction (LVEF), and NT-proBNP. Nine randomized controlled clinical trials were included. Dapagliflozin was reported to significantly decrease CV death/HHF (relative risk (RR): 0.75; 95% confidence interval (CI): 0.68-0.84), CV death (RR: 0.80; 95% CI: 0.68-0.93), and HHF (RR: 0.72; 95% CI: 0.63-0.83). There was no effect on hypoglycemia (RR: 0.69; 95% CI: 0.34-1.40), volume depletion (RR: 1.17; 95% CI: 0.97-1.41), urinary tract infection (RR: 0.82; 95% CI: 0.43-1.57), LVEF (WMD: 0.53; 95% CI: -4.04-5.09), or NT-proBNP (SMD: -0.66; 95% CI: -1.42-0.10). The risk of CV death/HHF, CV death, and HHF was lower among patients receiving dapagliflozin than patients receiving placebo.

Exosomal LINC00174 derived from vascular endothelial cells attenuates myocardial I/R injury via p53-mediated autophagy and apoptosis.

In this study, we aim to investigate the regulation of specific long non-coding RNAs (lncRNAs) on the progression of ischemia/reperfusion (I/R) injury. We identified and characterized the exosomes derived from mouse primary aortic endothelial cells. Subsequently, we found that these exosomes expressed typical exosomal markers and high levels of LINC00174, which significantly ameliorated I/R-induced myocardial damage and suppressed the apoptosis, vacuolation, and autophagy of myocardial cells. Mechanistic approaches revealed that LINC00174 directly interacted with SRSF1 to suppress the expression of p53, thus restraining the transcription of myocardin and repressing the activation of the Akt/AMPK pathway that was crucial for autophagy initiation in I/R-induced myocardial damage. Moreover, this molecular mechanism was verified by in vivo study. In summary, exosomal LINC00174 generated from vascular endothelial cells repressed p53-mediated autophagy and apoptosis to mitigate I/R-induced myocardial damage, suggesting that targeting LINC00174 may be a novel strategy to treat I/R-induced myocardial infarction.

Long non-coding RNA CASC7 is associated with the pathogenesis of heart failure via modulating the expression of miR-30c.

MiRNAs can be used as promising diagnostic biomarkers of heart failure, while lncRNAs act as competing endogenous RNAs of miRNAs. In this study, we collected peripheral blood monocytes from subjects with or without HF to explore the association between certain lncRNAs, miRNAs and HF. Heart failure patients with preserved or reduced ejection fraction were recruited for investigation. ROC analysis was carried out to evaluate the diagnostic values of certain miRNAs and lncRNAs in HF. Luciferase assays were used to study the regulatory relationship between above miRNAs and lncRNAs. LncRNA overexpression was used to explore the effect of certain miRNAs in H9C2 cells. Expression of miR-30c was significantly decreased in the plasma and peripheral blood monocytes of patients suffering from heart failure, especially in these with reduced ejection fraction. On the contrary, the expression of lncRNA-CASC7 was remarkably increased in the plasma and peripheral blood monocytes of patients suffering from heart failure. Both miR-30c and lncRNA-CASC7 expression showed a promising efficiency as diagnostic biomarkers of heart failure. Luciferase assays indicated that miR-30c played an inhibitory role in lncRNA-CASC7 and IL-11 mRNA expression. Moreover, the overexpression of lncRNA-CASC7 suppressed the expression of miR-30c while evidently increasing the expression of IL-11 mRNA and protein in H9C2 cells. This study clarified the relationship among miR-30c, lncRNA-CASC7 and IL-11 expression and the risk of heart failure and showed that lncRNA-CASC7 is potentially involved in the pathogenesis of HF via modulating the expression of miR-30c.