{"title":"Macrophage-Derived Exosomal MALAT1 Regulates Autophagy through miR-204-5p/ATG7 Axis in H9C2 Cardiomyocytes and Diabetic Rat Heart.","authors":"Kou-Gi Shyu, Bao-Wei Wang, Chun-Ming Pan, Wei-Jen Fang","doi":"10.6515/ACS.202505_41(3).20250224D","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Autophagy activity is tightly associated with cardiovascular disease development and progression. The effect of exosomal metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) derived from macrophages treated with high levels of glucose on autophagy in cardiomyocytes and diabetic hearts is not known. We investigated the effect of autophagy and its regulatory mechanisms on H9C2 cardiomyocytes and diabetic hearts by macrophage-derived exosomal MALAT1.</p><p><strong>Methods: </strong>Mouse macrophages and rat H9C2 cardiomyocytes were cultured, and exosomes were extracted from the culture media. A diabetic model was established through the injection of streptozotocin into adult male Wistar rats. Reverse transcription real-time quantitative polymerase chain reaction, Western blotting, immunohistochemical staining, autophagosome and/or autolysosome fluorescent cell staining, and luciferase activity assays were performed.</p><p><strong>Results: </strong>High glucose significantly enhanced exosomal MALAT1 expression in cultured H9C2 cells and macrophages. Macrophage-derived exosomes significantly increased autophagy-related 7 (ATG7) and decreased miR-204-5p expressions. Silencing MALAT1 by MALAT1 small interference RNA and the overexpression of wild-type miR-204-5p significantly decreased the ATG7 expression induced by macrophage-derived exosomes. MiR-204-5p significantly decreased MALAT1 and ATG7 luciferase activity in cultured H9C2 cells treated with macrophage-derived exosomes. Streptozotocin-induced diabetes mellitus and macrophage-derived exosomes significantly enhanced MALAT1 expression to inhibit miR204-5p expression in the rat hearts. Macrophage-derived exosomes significantly enhanced ATG7 expression in the streptozotocin-induced diabetic hearts.</p><p><strong>Conclusions: </strong>In conclusion, we discovered that exosomal MALAT1 derived from macrophages after high glucose treatment could sequester miR-204-5p, leading to the upregulation of ATG7 expression, and this was linked to the regulation of autophagy in H9C2 cardiomyocytes and streptozotocin-induced diabetic hearts.</p>","PeriodicalId":6957,"journal":{"name":"Acta Cardiologica Sinica","volume":"41 3","pages":"346-360"},"PeriodicalIF":1.8000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12099248/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Cardiologica Sinica","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.6515/ACS.202505_41(3).20250224D","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Autophagy activity is tightly associated with cardiovascular disease development and progression. The effect of exosomal metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) derived from macrophages treated with high levels of glucose on autophagy in cardiomyocytes and diabetic hearts is not known. We investigated the effect of autophagy and its regulatory mechanisms on H9C2 cardiomyocytes and diabetic hearts by macrophage-derived exosomal MALAT1.
Methods: Mouse macrophages and rat H9C2 cardiomyocytes were cultured, and exosomes were extracted from the culture media. A diabetic model was established through the injection of streptozotocin into adult male Wistar rats. Reverse transcription real-time quantitative polymerase chain reaction, Western blotting, immunohistochemical staining, autophagosome and/or autolysosome fluorescent cell staining, and luciferase activity assays were performed.
Results: High glucose significantly enhanced exosomal MALAT1 expression in cultured H9C2 cells and macrophages. Macrophage-derived exosomes significantly increased autophagy-related 7 (ATG7) and decreased miR-204-5p expressions. Silencing MALAT1 by MALAT1 small interference RNA and the overexpression of wild-type miR-204-5p significantly decreased the ATG7 expression induced by macrophage-derived exosomes. MiR-204-5p significantly decreased MALAT1 and ATG7 luciferase activity in cultured H9C2 cells treated with macrophage-derived exosomes. Streptozotocin-induced diabetes mellitus and macrophage-derived exosomes significantly enhanced MALAT1 expression to inhibit miR204-5p expression in the rat hearts. Macrophage-derived exosomes significantly enhanced ATG7 expression in the streptozotocin-induced diabetic hearts.
Conclusions: In conclusion, we discovered that exosomal MALAT1 derived from macrophages after high glucose treatment could sequester miR-204-5p, leading to the upregulation of ATG7 expression, and this was linked to the regulation of autophagy in H9C2 cardiomyocytes and streptozotocin-induced diabetic hearts.
期刊介绍：
Acta Cardiologica Sinica welcomes all the papers in the fields related to cardiovascular medicine including basic research, vascular biology, clinical pharmacology, clinical trial, critical care medicine, coronary artery disease, interventional cardiology, arrythmia and electrophysiology, atherosclerosis, hypertension, cardiomyopathy and heart failure, valvular and structure cardiac disease, pediatric cardiology, cardiovascular surgery, and so on. We received papers from more than 20 countries and areas of the world. Currently, 40% of the papers were submitted to Acta Cardiologica Sinica from Taiwan, 20% from China, and 20% from the other countries and areas in the world. The acceptance rate for publication was around 50% in general.
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