Retraction Notice to: miR-146a inhibits mitochondrial dysfunction and myocardial infarction by targeting cyclophilin D.

[This retracts the article DOI: 10.1016/j.omtn.2021.01.034.].

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.

Possible implication of miR-142-3p in coronary microembolization induced myocardial injury via ATXN1L/HDAC3/NOL3 axis.

This study aims to explore the mechanism underlying miR-142-3p regulating myocardial injury induced by coronary microembolization (CME) through ATXN1L. miR-142-3p overexpression or ATXN1L knockout adenovirus vectors were injected into rats before CME treatment. Cardiac functions were examined by echocardiography, and pathologies of myocardial tissues were assessed. Then, serum cTnI and IL-1ß contents and concentrations of IL-1ß and IL-18 in cell supernatant were measured. Immunofluorescence determined the localization of histone deacetylase 3 (HDAC3). The interaction between miR-142-3p and ATXN1L as well as the binding between HDAC3 and histone 3 (H3) was identified. The binding of ATXN1L and HDAC3 to NOL3 promoter was verified using ChIP. The levels of ATXN1L, NOL3, and miR-142-3p as well as apoptosis- and pyroptosis-related proteins and acetyl-histone 3 (ac-H3) were evaluated. CME treatment impaired the cardiac functions in rats and increased cTnI content. CME rats showed microinfarction foci in myocardial tissues. After CME treatment, miR-142-3p and NOL3 were modestly expressed while ATXN1L content was elevated, in addition to increases in apoptosis and pyroptosis. miR-142-3p overexpression or ATXN1L knockout alleviated CME-induced myocardial injury, cardiomyocyte apoptosis, and pyroptosis in myocardial tissues. miR-142-3p regulated ATXN1L expression in a targeted manner. In the cellular context, miR-142-3p overexpression attenuated apoptosis and pyroptosis in cardiomyocytes, which was partly counteracted by ATXN1L overexpression. ATXN1L functioned on cardiomyocytes by promoting deacetylation of H3 through HDAC3 and thus inhibited NOL3 expression. Inhibition of HDAC3 or overexpression of NOL3 ameliorated the promotive effects of ATXN1L on cardiomyocyte apoptosis and pyroptosis. In vivo and in vitro evidence in this study supported that miR-142-3p could attenuate CME-induced myocardial injury via ATXN1L/HDAC3/NOL3. HIGHLIGHTS: CME model witnessed aberrant expression of miR-142-3p, ATXN1L, and NOL3; miR-142-3p negatively regulated ATXN1L; miR-142-3p mediated CME-induced myocardial injury through ATXN1L; ATXN1L promoted deacetylation of H3 through HDAC3 and thus inhibited NOL3 expression; ATXN1L acted on cardiomyocyte apoptosis and pyroptosis through HDAC3/NOL3 axis.

LncRNA MALAT1 functions as a biomarker of no-reflow phenomenon in ST-segment elevation myocardial infarction patients receiving primary percutaneous coronary intervention.

MALAT1 was reported to sponge miR-30e, miR-126 and miR-155 in the pathogenesis of many diseases. Plasma miR-30e can indicate the risk of no-reflow during primary percutaneous coronary intervention (pPCI), while miR-126 can be used as a predictor of coronary slow flow phenomenon. In this study, we compared the diagnostic value of above genes in the prediction of no-reflow phenomenon in ST-segment elevation myocardial infarction (STEMI) subjects receiving pPCI. Quantitative real-time PCR, ELISA, Western blot and luciferase assays were performed to explore the regulatory relationship of MALAT1/miR-30e, MALAT1/miR-126, MALAT1/miR-155, miR-126/HPSE, and miR-155/EDN1. ROC analysis was carried out to evaluate the potential value of MALAT1, miRNAs and target genes in differentiating normal reflow and no-reflow in STEMI patients receiving pPCI. Elevated MALAT1, CRP, HPSE, and EDN1 expression and suppressed miR-30e, miR-155 and miR-126 expression was found in the plasma of STEMI patients receiving pPCI who were diagnosed with no-reflow phenomenon. ROC analysis showed that the expression of MALAT1, miR-30e, miR-126 and CRP could be used as predictive biomarkers to differentiate normal reflow and no-reflow in STEMI patients receiving pPCI. MALAT1 was found to suppress the expression of miR-30e, miR-126 and miR-155, and HPSE and EDN1 were respectively targeted by miR-126 and miR-155. This study demonstrated that MALAT1 could respectively sponge the expression of miR-30e, miR-126 and miR-155. And miR-30e, miR-126 and miR-155 respectively targeted CRP, HPSE and EDN1 negatively. Moreover, MALAT1 could function as an effective biomarker of no-reflow phenomenon in STEMI patients receiving pPCI.

MicroRNA-136-5p protects cardiomyocytes from coronary microembolization through the inhibition of pyroptosis.

This study investigated how miR-136-5p partially affected cardiomyocyte pyroptosis in rats with coronary microembolization (CME). The cardiac function and structure of rats with CME were evaluated using echocardiography, hematoxylin and eosin staining, Masson staining, and troponin I level. Pyroptosis was induced by lipopolysaccharide (LPS) in isolated rat cardiomyocytes and evaluated by the expression of caspase-1, NOD-like receptor family pyrin domain-containing 3, interleukin-1ß, and gasdermin D-N. After cell transfection, the expression of Ataxin-1 like (ATXN1L), pyrin domain-containing 1 (PYDC1), and pyroptosis-related proteins was assessed. Dual-luciferase reporter and immunoprecipitation assays were used to verify the relationships among miR-136-5p, ATXN1L, and capicua (CIC). MiR-136-5p was under-expressed, whereas ATXN1L was overexpressed in rats with CME and in LPS-treated primary cardiomyocytes. MiR-136-5p targeted ATXN1L, and ATXN1L bound to CIC to suppress PYDC1 expression. MiR-136-5p overexpression suppressed pyroptosis by inhibiting the binding of ATXN1L with CIC and promoting PYDC1 expression, which was reversed by simultaneous elevation of ATXN1L. In conclusion, miR-136-5p suppressed pyroptosis by upregulating PYDC1 via ATXN1L/CIC axis, thereby attenuating cardiac damage caused by CME.

MiR-32-3p Regulates Myocardial Injury Induced by Microembolism and Microvascular Obstruction by Targeting RNF13 to Regulate the Stability of Atherosclerotic Plaques.

This study aimed to explore the molecular mechanism of myocardial protection. The effects of miR-32-3p and ring finger protein 13 (RNF13) on endoplasmic reticulum (ER) stress-induced apoptosis of A-10 cells and human umbilical vein endothelial cells (HUVEC) were detected using flow cytometry. The effects of miR-32-3p and phenylbutyric acid (PBA) on plaque instability and myocardial tissue injury in rats were investigated after establishment of arterial plaque model and embolization model and treatment with miR-32-3p-antagomir and PBA. RNF13, which was differentially expressed in myocardial infarction, was the direct target gene of miR-32-3p. MiR-32-3p inhibited RNF13 expression and targeted RNF13 to inhibit ER stress-induced cell apoptosis. Furthermore, inhibiting miR-32-3p expression induced arterial plaque instability by reducing survival, increasing pathological lesions in arterial tissue, up-regulating ER stress-related proteins, and regulating the expressions of apoptosis-related proteins in the model rats. However, PBA reversed the effects of miR-32-3p-antagomir on the model rats. MiR-32-3p regulates myocardial injury induced by micro-embolism and micro-vascular obstruction by targeting RNF13 to regulate the stability of atherosclerotic plaques.

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.

miR-146a inhibits mitochondrial dysfunction and myocardial infarction by targeting cyclophilin D.

Increasing evidence suggests that mitochondrial microRNAs (miRNAs) are implicated in the pathogenesis of cardiovascular diseases; however, their roles in ischemic heart disease remain unclear. Herein, we demonstrate that miR-146a is enriched in the mitochondrial fraction of cardiomyocytes, and its level significantly decreases after ischemic reperfusion (I/R) challenge. Cardiomyocyte-specific knockout of miR-146a aggravated myocardial infarction, apoptosis, and cardiac dysfunction induced by the I/R injury. Overexpression of miR-146a suppressed anoxia/reoxygenation-induced cardiomyocyte apoptosis by inhibiting the mitochondria-dependent apoptotic pathway and increasing the Bcl-2/Bax ratio. miR-146a overexpression also blocked mitochondrial permeability transition pore opening and attenuated the loss of mitochondrial membrane potential and cytochrome c leakage; meanwhile, miR-146a knockdown elicited the opposite effects. Additionally, miR-146a overexpression decreased cyclophilin D protein, not mRNA, expression. The luciferase reporter assay revealed that miR-146a binds to the coding sequence of the cyclophilin D gene. Restoration of cyclophilin D reversed the inhibitory action of miR-146a on cardiomyocyte apoptosis. Furthermore, cardiomyocyte-specific cyclophilin D deletion completely abolished the exacerbation of myocardial infarction and apoptosis observed in miR-146a cardiomyocyte-deficient mice. Collectively, these findings demonstrate that nuclear miR-146a translocates into the mitochondria and regulates mitochondrial function and cardiomyocyte apoptosis. Our study unveils a novel role for miR-146a in ischemic heart disease.

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.