Abstract
Coronary microembolization (CME) commonly develops as a complication after percutaneous coronary intervention (PCI), and associated inflammation is a leading driver of myocardial damage. Cardiomyocyte loss in the context of ischemic myocardial disease has been linked to inflammatory pyroptotic cell death. Additionally, miR-200a-3p dysregulation has been linked to myocardial ischemia-reperfusion and many other pathological conditions. However, how miR-200a-3p impacts cardiomyocyte pyroptosis in the context of CME remains to be assessed. Herein, a rat model of CME was established via the injection of microembolic spheres into the left ventricle. When myocardial tissue samples from these rats were analyzed, miR-200a-3p levels were markedly decreased, whereas thioredoxin-interacting protein (TXNIP) levels were increased. The ability of miR-200a-3p to directly target TXNIP and to control its expression was confirmed via dual-luciferase reporter assay. Adeno-associated virus serotype 9-pre-miR-200a-3p (AAV-miR-200a-3p) construct transfection was then employed as a means of upregulating this miRNA in CME model rats. Subsequent assays, including echocardiography, enzyme-linked immunosorbent assays (ELISAs), hematoxylin-eosin (H&E) staining, hematoxylin-basic fuchsin-picric acid (HBFP) staining, TdT-mediated dUTP nick-end labeling (TUNEL) staining, immunofluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting revealed that miR-200a-3p overexpression inhibited cardiomyocyte pyroptosis and alleviated CME-induced myocardial injury by inhibiting the TXNIP/NOD-like receptor family pyrin domain-containing 3 (NLRP3) pathway. The ability of miR-200a-3p to protect against CME-induced myocardial injury thus highlights a novel approach to preventing or treating such myocardial damage in clinical settings.
Highlights
Coronary microembolization (CME) is a serious complication of percutaneous coronary intervention (PCI) that is independently predictive of negative cardiac events and poor long-term patient outcomes in the context of the slow- or no-reflow phenomenon [1]
These findings indicated that our CME model had been established successfully and that it induced myocardial injury in experimental rats
We evaluated the role of miR-200a-3p as a regulator of CME-induced cardiomyocyte pyroptosis in rats
Summary
Coronary microembolization (CME) is a serious complication of percutaneous coronary intervention (PCI) that is independently predictive of negative cardiac events and poor long-term patient outcomes in the context of the slow- or no-reflow phenomenon [1]. The acute phase of CME can drive myocardial inflammation, apoptotic cell death, and necrosis, with subsequent cardiac systolic dysfunction and myocardial injury being promoted in large part by these inflammatory processes [3, 4]. Pyroptosis is a form of inflammatory cell death that is physiologically distinct from apoptosis or necrosis, and that is driven by pro-inflammatory factors and the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3)/caspase-1 signaling pathway [5]. Gasdermin D (GSDMD) can be cleaved by caspase-1, resulting in the release of its N-terminal poreforming domain (GSDMD-N), which is subsequently inserted into cellular membranes to facilitate inflammatory factor release, cellular swelling, and membrane rupture [8]. Pyroptosis has previously been linked to myocardial infarction, myocardial ischemia-reperfusion injury, diabetic cardiomyopathy, and heart failure [9], but its mechanistic role in the context of CME remains to be defined and warrants further study in an effort to define novel approaches to preventing CME-induced myocardial damage
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