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Title:
METTL14 promotes doxorubicin-induced cardiomyocyte ferroptosis by regulating the KCNQ1OT1-miR-7-5p-TFRC axis | Cell Biology and Toxicology
Description:
Doxorubicin (DOX) has toxic effects on the heart, causing cardiomyopathy and heart injury, but the underlying mechanisms of these effects require further investigation. This study investigated the role of DOX in promoting ferroptosis to induce myocardial injury. AC16 cardiomyocyte and neonatal rat ventricle cardiomyocytes were used as an in vitro model to study the molecules involved in myocardial injury using gene silencing, ectopic expression, and RNA immunoprecipitation. Messenger RNA and protein level analyses showed that DOX treatment resulted in the upregulation of methyltransferase-like 14 (METTL14), which catalyzes the m6A modification of the long non-coding RNA KCNQ1OT1, a miR-7-5p sponge. The RNA-binding protein IGF2BP1 is associated with KCNQ1OT1 to increase its stability and robustly inhibit miR-7-5p activity. Furthermore, a lack of miR-7-5p expression led to increased levels of transferrin receptor, promoting the uptake of iron and production of lipid reactive oxygen species and demonstrating that DOX-induced ferroptosis occurs in AC16 cells. Additionally, we found that miR-7-5p targets METTL14 in AC16 cells. Meanwhile, the role of METTL14/KCNQ1OT1/miR-7-5p axis in regulating ferroptosis in neonatal rat ventricle cardiomyocytes was also confirmed. Our results indicate that selectively inhibiting ferroptosis mediated by a METTL14/KCNQ1OT1/miR-7-5p positive feedback loop in cardiomyocytes could provide a new therapeutic approach to control DOX-induced cardiac injury. Graphical abstract
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Keywords {š}
pubmed, article, google, scholar, cas, cell, wang, central, ferroptosis, rna, cancer, zhang, cardiomyocytes, noncoding, mirp, heart, biol, liu, yang, kcnqot, chen, jiang, long, res, mettl, doxorubicininduced, role, death, mol, human, shanghai, content, data, cardiomyopathy, silencing, doxinduced, cells, access, nmethyladenosine, targeting, failure, zhou, privacy, cookies, analysis, information, cardiomyocyte, zhuang, yan, zeng,
Topics {āļø}
kcnq1ot1-mir-7-5p-tfrc axis mettl14/kcnq1ot1/mir-7-5p axis trem1/nfāĪŗb signaling pathway rna-binding protein igf2bp1 mir-7-5p targets mettl14 n6-methyladenosine rna modification rna n6-methyladenosine modification month download article/chapter dox-induced ferroptosis occurs dox-induced human cardiomyocytes mir-7-5p expression led mammalian n6-methyladenosine doxorubicin-induced ferroptosis distinct rna-binding domains igf2 mrna-binding proteins mitochondria-dependent ferroptosis plays mir-7-5p sponge mir-26b-5p sponging mir-7-5p doxorubicin-induced cardiomyopathy myocardial ischemia-reperfusion injury mir-7ā5p expression article cell biology key ceramide-synthesizing enzyme coding rna kcnq1ot1 long noncoding rnas acute heart failure full article pdf related subjects targeting tfrc n6-methyladenosine mir-7-5p heart failure progression privacy choices/manage cookies check access lipid composition instant access autophagic degradation process messenger rna modifications competing endogenous rna dox treatment resulted transferrin regulate ferroptosis ļæ½ mettl14 induces induce myocardial injury genital system tumors silencing long article zhuang nonapoptotic cell death programmed cell death cell death differ
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headline:METTL14 promotes doxorubicin-induced cardiomyocyte ferroptosis by regulating the KCNQ1OT1-miR-7-5p-TFRC axis
description:Doxorubicin (DOX) has toxic effects on the heart, causing cardiomyopathy and heart injury, but the underlying mechanisms of these effects require further investigation. This study investigated the role of DOX in promoting ferroptosis to induce myocardial injury. AC16 cardiomyocyte and neonatal rat ventricle cardiomyocytes were used as an in vitro model to study the molecules involved in myocardial injury using gene silencing, ectopic expression, and RNA immunoprecipitation. Messenger RNA and protein level analyses showed that DOX treatment resulted in the upregulation of methyltransferase-like 14 (METTL14), which catalyzes the m6A modification of the long non-coding RNA KCNQ1OT1, a miR-7-5p sponge. The RNA-binding protein IGF2BP1 is associated with KCNQ1OT1 to increase its stability and robustly inhibit miR-7-5p activity. Furthermore, a lack of miR-7-5p expression led to increased levels of transferrin receptor, promoting the uptake of iron and production of lipid reactive oxygen species and demonstrating that DOX-induced ferroptosis occurs in AC16 cells. Additionally, we found that miR-7-5p targets METTL14 in AC16 cells. Meanwhile, the role of METTL14/KCNQ1OT1/miR-7-5p axis in regulating ferroptosis in neonatal rat ventricle cardiomyocytes was also confirmed. Our results indicate that selectively inhibiting ferroptosis mediated by a METTL14/KCNQ1OT1/miR-7-5p positive feedback loop in cardiomyocytes could provide a new therapeutic approach to control DOX-induced cardiac injury.
datePublished:2021-10-14T00:00:00Z
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Doxorubicin
Ferroptosis
N6-Methyladenosine
METTL14
lncRNAs
KCNQ1OT1
IGF2BP1
miR-7-5p
TFRC
Cardiomyocytes
Cell Biology
Pharmacology/Toxicology
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headline:METTL14 promotes doxorubicin-induced cardiomyocyte ferroptosis by regulating the KCNQ1OT1-miR-7-5p-TFRC axis
description:Doxorubicin (DOX) has toxic effects on the heart, causing cardiomyopathy and heart injury, but the underlying mechanisms of these effects require further investigation. This study investigated the role of DOX in promoting ferroptosis to induce myocardial injury. AC16 cardiomyocyte and neonatal rat ventricle cardiomyocytes were used as an in vitro model to study the molecules involved in myocardial injury using gene silencing, ectopic expression, and RNA immunoprecipitation. Messenger RNA and protein level analyses showed that DOX treatment resulted in the upregulation of methyltransferase-like 14 (METTL14), which catalyzes the m6A modification of the long non-coding RNA KCNQ1OT1, a miR-7-5p sponge. The RNA-binding protein IGF2BP1 is associated with KCNQ1OT1 to increase its stability and robustly inhibit miR-7-5p activity. Furthermore, a lack of miR-7-5p expression led to increased levels of transferrin receptor, promoting the uptake of iron and production of lipid reactive oxygen species and demonstrating that DOX-induced ferroptosis occurs in AC16 cells. Additionally, we found that miR-7-5p targets METTL14 in AC16 cells. Meanwhile, the role of METTL14/KCNQ1OT1/miR-7-5p axis in regulating ferroptosis in neonatal rat ventricle cardiomyocytes was also confirmed. Our results indicate that selectively inhibiting ferroptosis mediated by a METTL14/KCNQ1OT1/miR-7-5p positive feedback loop in cardiomyocytes could provide a new therapeutic approach to control DOX-induced cardiac injury.
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Ferroptosis
N6-Methyladenosine
METTL14
lncRNAs
KCNQ1OT1
IGF2BP1
miR-7-5p
TFRC
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Pharmacology/Toxicology
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general
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