Abstract
Coronary microembolization (CME) is a complicated problem that commonly arises in the context of coronary angioplasty. The lncRNA taurine-up regulated gene 1 (TUG1), significantly contributes to cardiovascular diseases; however, its contribution to CME-induced myocardial damage remains elusive. Herein, we establish the rat CME model and investigate the role of TUG1 in CME. The cell viability was evaluated via CCK-8 assay. Serum and cell culture supernatant samples were evaluated via ELISA. The dual luciferase reporter (DLR) assay, RIP, and RNA-pull down were conducted to validate the associations between TUG1 and miR-186-5p as well as miR-186-5p and XIAP. The expression of TUG1, miR-186-5p, and XIAP mRNA were determined by RT-qPCR, and proteins were evaluated via immuneblotting. As a result, TUG1 and XIAP were significantly down-regulated, and the miR-186-5p level was found to be remarkably up-regulated in CME myocardial tissues. Overexpression of TUG1 alleviated CME-induced myocardial injury and pyroptosis, whereas TUG1 knockdown showed the opposite effects. The DLR assay, RIP, and RNA-pull down results reveal that TUG1 directly targets miR-186-5p and miR-186-5p directly targets XIAP. In vitro rescue experiments show that TUG1 overexpression alleviates LPS-caused cardiomyocyte injury and pyroptosis via sponging miR-186-5p and regulating XIAP, and depression of miR-186-5p reduces LPS-induced cardiomyocyte injury and pyroptosis by targeting XIAP. Concludingly, the overexpression of TUG1 alleviates NLRP3 inflammasome-mediated cardiomyocyte pyroptosis through targeting the miR-186-5p/XIAP axis in CME-induced myocardial injury.
Highlights
Coronary microembolization (CME) is the most predominant complication in percutaneous coronary intervention (PCI) therapy [1, 2]
The analysis of Pearson’s correlation demonstrated that taurine-up regulated gene 1 (TUG1) expression was considerably associated with LVEF, but negatively correlated with the expression of NLRP3, IL-18, and IL-1β mRNA (Figure 1F). These results reveal that TUG1 may contribute to CME-activated myocardial injury and pyroptosis
Expression of pyroptosis-associated proteins was dramatically down regulated by the inhibition of miR-186-5p, which were remarkably reversed by co-transfection with shXIAP (Figures 7E–J). These results indicate that the inhibition of miR-186-5p could decrease the hypoxia-initiated cardiomyocyte injury and pyroptosis, and the process might be through the regulation of X-linked inhibitor of apoptosis protein (XIAP)
Summary
Coronary microembolization (CME) is the most predominant complication in percutaneous coronary intervention (PCI) therapy [1, 2]. The risk of CME in perioperative PCI has been revealed as up to 45% in high-risk patients [3]. CME may result in myocardial malfunction, including myocardial infarction, arrhythmias, heart attack, and reduction of coronary flow reserve fraction [4,5,6]. Pyroptosis is an inflammatory-mediated cell death, which is stimulated via downstream-activated caspase-1 and results in cellular rupture and the release of proinflammatory cytokines [7, 8]. Suppressing cardiomyocyte pyroptosis might be a candidate target for CME. The molecular mechanisms governing cardiomyocyte pyroptosis in the context of CME are not clearly understood
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