Abstract
BackgroundReceptor-interacting serine-threonine kinase 3 (RIPK3)-mediated necroptosis has been implicated in the progression of myocardial infarction (MI), but the underlying mechanisms, particularly whether microRNAs (miRNAs) are involved, remain largely unknown.ResultsA microarray analysis was used to screen for miR-325-3p expression in myocardial tissues from MI mice, and the expression was confirmed with qRT-PCR. The levels of myocardial enzymes were measured using commercial kits, and an echocardiography system was utilized for the detection of cardiac function parameters. The pathological features and infarction sizes of cardiac tissues were examined using H&E, TCC and Masson’s trichrome staining, and the amount of cell apoptosis was determined using an in situ TUNEL assay. Cardiomyocytes were isolated and then subjected to hypoxia induction in vitro. The expression of the RIPK1, RIPK3 and phosphorylated MLKL (p-MLKL) proteins was measured using a Western blot. The mouse cardiomyocyte cell viability was analyzed by an MTT assay. The mRNA target of miR-325-3p was predicted using TargetScan v7.2 and then validated using a dual-luciferase reporter assay. The overexpression of miR-325-3p evidently decreased the expression levels of lactate dehydrogenase (LDH), phosphocreatine kinase (CK), superoxide dismutase (SOD) and malondialdehyde (MDA), inhibited left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD), and promoted left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVES). In addition, miR-325-3p overexpression attenuated the degree of injury to the cardiac tissue, decreased the infarct sizes and downregulated the expression of the necrosis-related proteins RIPK1, RIPK3 and p-MLKL.ConclusionsThe RIPK1/RIPK3/p-MLKL axis-induced necroptosis that occurred during MI was mediated by a miRNA module, miR-325-3p, which can effectively ameliorate the symptoms of MI by suppressing the expression of RIPK3.
Highlights
Receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated necroptosis has been implicated in the progression of myocardial infarction (MI), but the underlying mechanisms, whether microRNAs are involved, remain largely unknown
Correlation between miR‐325‐3p and serum myocardial enzymes in MI mice Compared to the sham-operated mice, the serum levels of lactate dehydrogenase (LDH) (Fig. 2a), phosphocreatine kinase (CK) (Fig. 2b) and malondialdehyde (MDA) (Fig. 2c) were significantly increased in MI mice (P < 0.01), and they reached their highest level when the activity of miR-325-3p was suppressed by antagomiR325-3p
The expression levels of RIPK1, RIPK3 and phosphorylated MLKL were increased in the heart tissue of MI mice and hypoxia-induced cardiomyocytes, only the knockdown of RIPK3 by a specific siRNA could significantly increase the viability of cardiomyocytes cultured under hypoxic conditions to the viability of cells cultured under normal conditions
Summary
Receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated necroptosis has been implicated in the progression of myocardial infarction (MI), but the underlying mechanisms, whether microRNAs (miR‐ NAs) are involved, remain largely unknown. Myocardial infarction is a leading cause of mortality worldwide and is usually caused by the pathological coronary artery occlusion [1, 2]. In China, according to the estimates from World Bank, more than 23 million will experience myocardial infarction annually by 2030. Risk factors, including smoking, metabolic syndrome and hypertension, could cause the higher morbidity and mortality seen in myocardial infarction cases [4]. The following mechanisms have been implicated in the progression of myocardial infarction: kallikrein-kinin [5], carbon metabolism [6], and renin–angiotensin–aldosterone system [4]. In recent years, increasing evidence has suggested that programmed necrosis ( termed necroptosis, a novel mechanism of cell death that combines the features of necrosis and apoptosis) is closely related to various
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
