Bing Gao, Tiantian Gong, Zhuocao Qi, Lan Li, Pan Liu, Ran Xia, Lingji Li, Jing Wang
{"title":"心肌细胞的过度自噬促进了铁蛋白沉积,并加剧了心肌梗死状态下的心力衰竭","authors":"Bing Gao, Tiantian Gong, Zhuocao Qi, Lan Li, Pan Liu, Ran Xia, Lingji Li, Jing Wang","doi":"10.5114/aoms/188719","DOIUrl":null,"url":null,"abstract":"This study investigates the molecular mechanisms by which excessive autophagy exacerbates post-myocardial infarction heart failure(post-MI HF) through nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and ferroptosis.We developed a post-MI heart failure model in Sprague-Dawley rats via coronary artery ligation, alongside an in vitro heart failure model using hypoxia/reoxygenation-stimulated H9C2 cells. Intervention with rapamycin (autophagy activator), 3-methyladenine (autophagy inhibitor), desferrioxamine, and ferredoxin-1(ferroptosis inhibitors). Various techniques, including echocardiography, immunofluorescence colocalization, C11 BODIPY 581/591 staining, flow cytometry, transmission electron microscopy, western blotting, and RT-qPCR, were employed.In vivo analyses revealed that NCOA4-mediated ferritinophagy and ferroptosis are significant in post-MI HF. Manipulating autophagy through rapamycin and 3-methyladenine influenced the expression of NCOA4 and glutathione peroxidase 4 (GPX4), subsequently affecting ferroptosis and modulating heart failure severity. Our in vitro experiments corroborated these findings, demonstrating that heightened autophagy amplifies NCOA4 expression, which in turn fosters ferroptosis and exacerbates myocardial injury. Interestingly, silencing of NCOA4 partially mitigated autophagy-induced iron deficiency, indicating a crucial intersection between autophagy and iron metabolism. Moreover, the cardioprotective effects observed following NCOA4 silencing were negated by concurrent GPX4 silencing.Our findings elucidate that autophagy precedes NCOA4 in its regulatory pathway and directly influences ferritinophagy. Enhanced autophagy augments intracellular free iron and unstable iron pools, triggering lipid peroxidation through ferritinophagy, which promotes ferroptosis and impairs cardiac function. These insights offer a novel scientific basis for developing therapeutic strategies for heart failure post-MI HF.","PeriodicalId":3,"journal":{"name":"ACS Applied Electronic Materials","volume":"128 22","pages":""},"PeriodicalIF":4.3000,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Excessive autophagy of myocardial cells promotes ferroptosis and exacerbates heart failure in the state of myocardial infarction\",\"authors\":\"Bing Gao, Tiantian Gong, Zhuocao Qi, Lan Li, Pan Liu, Ran Xia, Lingji Li, Jing Wang\",\"doi\":\"10.5114/aoms/188719\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"This study investigates the molecular mechanisms by which excessive autophagy exacerbates post-myocardial infarction heart failure(post-MI HF) through nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and ferroptosis.We developed a post-MI heart failure model in Sprague-Dawley rats via coronary artery ligation, alongside an in vitro heart failure model using hypoxia/reoxygenation-stimulated H9C2 cells. Intervention with rapamycin (autophagy activator), 3-methyladenine (autophagy inhibitor), desferrioxamine, and ferredoxin-1(ferroptosis inhibitors). Various techniques, including echocardiography, immunofluorescence colocalization, C11 BODIPY 581/591 staining, flow cytometry, transmission electron microscopy, western blotting, and RT-qPCR, were employed.In vivo analyses revealed that NCOA4-mediated ferritinophagy and ferroptosis are significant in post-MI HF. Manipulating autophagy through rapamycin and 3-methyladenine influenced the expression of NCOA4 and glutathione peroxidase 4 (GPX4), subsequently affecting ferroptosis and modulating heart failure severity. Our in vitro experiments corroborated these findings, demonstrating that heightened autophagy amplifies NCOA4 expression, which in turn fosters ferroptosis and exacerbates myocardial injury. Interestingly, silencing of NCOA4 partially mitigated autophagy-induced iron deficiency, indicating a crucial intersection between autophagy and iron metabolism. Moreover, the cardioprotective effects observed following NCOA4 silencing were negated by concurrent GPX4 silencing.Our findings elucidate that autophagy precedes NCOA4 in its regulatory pathway and directly influences ferritinophagy. Enhanced autophagy augments intracellular free iron and unstable iron pools, triggering lipid peroxidation through ferritinophagy, which promotes ferroptosis and impairs cardiac function. 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Excessive autophagy of myocardial cells promotes ferroptosis and exacerbates heart failure in the state of myocardial infarction
This study investigates the molecular mechanisms by which excessive autophagy exacerbates post-myocardial infarction heart failure(post-MI HF) through nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and ferroptosis.We developed a post-MI heart failure model in Sprague-Dawley rats via coronary artery ligation, alongside an in vitro heart failure model using hypoxia/reoxygenation-stimulated H9C2 cells. Intervention with rapamycin (autophagy activator), 3-methyladenine (autophagy inhibitor), desferrioxamine, and ferredoxin-1(ferroptosis inhibitors). Various techniques, including echocardiography, immunofluorescence colocalization, C11 BODIPY 581/591 staining, flow cytometry, transmission electron microscopy, western blotting, and RT-qPCR, were employed.In vivo analyses revealed that NCOA4-mediated ferritinophagy and ferroptosis are significant in post-MI HF. Manipulating autophagy through rapamycin and 3-methyladenine influenced the expression of NCOA4 and glutathione peroxidase 4 (GPX4), subsequently affecting ferroptosis and modulating heart failure severity. Our in vitro experiments corroborated these findings, demonstrating that heightened autophagy amplifies NCOA4 expression, which in turn fosters ferroptosis and exacerbates myocardial injury. Interestingly, silencing of NCOA4 partially mitigated autophagy-induced iron deficiency, indicating a crucial intersection between autophagy and iron metabolism. Moreover, the cardioprotective effects observed following NCOA4 silencing were negated by concurrent GPX4 silencing.Our findings elucidate that autophagy precedes NCOA4 in its regulatory pathway and directly influences ferritinophagy. Enhanced autophagy augments intracellular free iron and unstable iron pools, triggering lipid peroxidation through ferritinophagy, which promotes ferroptosis and impairs cardiac function. These insights offer a novel scientific basis for developing therapeutic strategies for heart failure post-MI HF.
期刊介绍:
ACS Applied Electronic Materials is an interdisciplinary journal publishing original research covering all aspects of electronic materials. The journal is devoted to reports of new and original experimental and theoretical research of an applied nature that integrate knowledge in the areas of materials science, engineering, optics, physics, and chemistry into important applications of electronic materials. Sample research topics that span the journal's scope are inorganic, organic, ionic and polymeric materials with properties that include conducting, semiconducting, superconducting, insulating, dielectric, magnetic, optoelectronic, piezoelectric, ferroelectric and thermoelectric.
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