Coronary microembolization (CME) occurs when atherosclerotic plaque debris is detached during the treatment of acute coronary syndrome with Percutaneous Coronary Intervention (PCI). The complications of distal microvascular embolism, including local myocardial inflammation, are the main causes of myocardial damage and are a strong predictor of poor long-term prognosis and major cardiac adverse events. microRNAs (miRNAs) are involved in the pathophysiological processes of cardiovascular inflammatory diseases. Dysregulation of microRNA (miR)-26a-5p, in particular, is associated with a variety of cardiovascular diseases. However, the role of miR-26a-5p in CME-induced myocardial injury is unclear. In this study, we developed an animal model of CME by injecting microembolic balls into the left ventricle of rats and found that miR-26a-5p expression decreased in myocardial tissue in response. Using a miR-26a-5p mimic, echocardiography, hematoxylin-eosin staining, and Western blot analysis we found that the diminished cardiac function and myocardial inflammation induced by CME is alleviated by miR-26a-5p overexpression.Furthermore, our results show that inhibitors of miR-26a-5p have the opposite effect. In addition, in vitro experiments using real-time PCR, Western blot analysis, and a dual luciferase reporter gene show that HMGA1 is a target gene of miR-26a-5p. Thus, overexpression of miR-26a-5p could be a novel therapy to improve CME-induced myocardial damage.
K E Y W O R D Scoronary artery microembolization, HMGA1, inflammation, miR-26a-5p, myocardial injury
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.
Myocardial infarction (MI) is a life-threatening cardiac event that results in extreme damage to the heart muscle. The Wnt signaling pathway has been implicated in the development of heart diseases. Hence, the current study aimed to investigate the role of microRNA (miRNA) in association with the Wnt signaling pathway to identify potential candidates for MI therapy. Differentially expressed miRNAs associated with MI occurrence were screened, and miR-494 was selected for subsequent experiments. Sprague-Dawley rats were included to establish a MI model via intraperitoneal injection of 0.1 mg/kg atropine sulfate and 40 mg/kg pentobarbital sodium. Then, the interaction between miR-494 and LRG1 was identified. The effect of miR-494 on expression of the Wnt signaling pathway-related genes, proliferation, migration, and invasion ability of fibroblasts and vascular endothelial cells (VECs) was subsequently evaluated through a series of gain- and loss-of-function experiments. The results revealed that miR-494 was poorly expressed and LRG1 was highly expressed in MI rats. miR-494 targets and downregulates LRG1, which resulted in the inactivation of the Wnt signaling pathway and promoted proliferation, migration, and invasion ability of fibroblasts and VECs. In conclusion, this study provided evidence suggesting that overexpressed miR-494 could potentially promote the proliferation, migration, and invasion of fibroblasts and VECs in MI through the inactivation of the Wnt signaling pathway by binding to LRG1.
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Coronary microembolization (CME) is a common complication seen during primary percutaneous coronary intervention (pPCI). CME-induced myocardiac inflammation is the primary cause of myocardiac injury. Dysregulated miR-142-3p has been implicated in multiple cardiovascular diseases and is significantly downregulated in CME-induced myocardial injury. However, the role of miR-142-3p in CME-induced myocardial injury is unclear. This study herein built a porcine CME model by infusing microembolization spheres into the left anterior descending branch via a microcatheter, and detected the downregulation of miR-142-3p in the myocardial tissues of CME pigs. Echocardiography, hematoxylin basic fuchsin picric acid (HBFP) staining, and western blotting of NF-κB p65, TNF-α, IL-1β, and IL-6 showed that the pharmacological overexpression of miR-142-3p using agomiR has improved cardiac function and attenuated CME-induced myocardiac inflammatory response, while its inhibition using antagomiR demonstrated inverse effects. Moreover, in vitro experiments demonstrated IRAK-1 as a direct target gene of miR-142-3p. Luciferase reporter assays, quantitative real-time polymerase chain reaction and western blotting demonstrated its effects in controlling the inflammation of cardiomyocytes. It is noteworthy that miR-142-3p was found to be decreased in the plasma of STEMI patients undergoing pPCI with no-reflow, indicating a potential clinical relevance of miR-142-3p. The receiver–operator characteristic curve indicated that plasma miR-142-3p might be an independent predictor of no-reflow during pPCI in patients with STEMI. Therefore, overexpression of miR-142-3p acts as a novel therapy for CME-induced myocardial injury.
Cardiomyocyte apoptosis is a key factor in the deterioration of cardiac function after coronary microembolization (CME). Nicorandil (NIC) affects myocardial injury, which may be related to the inhibition of apoptosis. However, the specific mechanism of cardioprotection has not been elucidated. Therefore, we analyzed the impact of NIC on cardiac function in rats subjected to CME and its effect on the high‐temperature requirement peptidase 2/X‐linked inhibitor of apoptosis protein/poly ADP‐ribose polymerase (HtrA2/XIAP/PARP) pathway. Sprague Dawley rats were divided into four groups: Sham, CME, CME + NIC, and CME + UCF. Echocardiography was performed 9 hours after CME. Myocardial injury markers were evaluated in blood samples, and the heart tissue was collected for hematoxylin‐eosin staining, hematoxylin basic fuchsin picric acid staining staining, TdT‐mediated DUTP nick end labeling (TUNEL) staining, Western blot analysis of the HtrA2/XIAP/PARP pathway, and transmission electron microscopy. NIC ameliorated cardiac dysfunctioncaused by CME and reduced serum levels of CK‐MB and LDH. In addition, NIC decreased myocardial microinfarct size and apoptotic index. NIC reduced the Bax/Bcl‐2 ratio, levels of cleaved caspase 3/9, cytoplasmic HtrA2, and cleaved PARP, and increased the level of XIAP. The effects of NIC were similar to those of the HtrA2 inhibitor, UCF101. This study demonstrated that NIC reduces CME‐induced myocardial injury, reduces mitochondrial damage, and improves myocardial function. The reduction in cardiomyocyte apoptosis by NIC may be mediated by the HtrA2/XIAP/PARP signaling pathway.
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