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.

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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.

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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.