{"corpus_id":51702450,"paper_sha":"c1061aa2b8ca4fc4add037e7318ce44da784f424","doi":"10.1159/000491896","arxiv_id":null,"pmid":30025410,"pmcid":null,"mag_id":2883087878,"dblp_id":null,"acl_id":null,"title":"MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity","year":2018,"publication_date":"2018-07-19","venue":"Cellular Physiology and Biochemistry","journal":{"name":"Cellular Physiology and Biochemistry","pages":"692 - 704","volume":"48"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article"],"s2_fields_of_study":["Biology","Medicine"],"reference_count":36,"citation_count":65,"influential_citation_count":7,"is_open_access":true,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":[{"d":"3' Untranslated Regions","mj":false,"ui":"D020413"},{"d":"Animals","mj":false,"ui":"D000818"},{"d":"Antagomirs","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D000070416"},{"d":"Antibiotics, Antineoplastic","mj":false,"qs":[{"q":"toxicity","mj":true,"ui":"Q000633"}],"ui":"D000903"},{"d":"Apoptosis","mj":false,"qs":[{"q":"drug effects","mj":true,"ui":"Q000187"}],"ui":"D017209"},{"d":"Base Sequence","mj":false,"ui":"D001483"},{"d":"Caspase 3","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D053148"},{"d":"Caspase 9","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D053453"},{"d":"Doxorubicin","mj":false,"qs":[{"q":"toxicity","mj":true,"ui":"Q000633"}],"ui":"D004317"},{"d":"Heart","mj":false,"qs":[{"q":"drug effects","mj":false,"ui":"Q000187"}],"ui":"D006321"},{"d":"Male","mj":false,"ui":"D008297"},{"d":"MicroRNAs","mj":false,"qs":[{"q":"antagonists & inhibitors","mj":false,"ui":"Q000037"},{"q":"genetics","mj":false,"ui":"Q000235"},{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D035683"},{"d":"Mitochondria","mj":false,"qs":[{"q":"drug effects","mj":false,"ui":"Q000187"},{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D008928"},{"d":"Myocardium","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D009206"},{"d":"Myocytes, Cardiac","mj":false,"qs":[{"q":"cytology","mj":false,"ui":"Q000166"},{"q":"drug effects","mj":false,"ui":"Q000187"},{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D032383"},{"d":"Proto-Oncogene Proteins c-bcl-2","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D019253"},{"d":"Rats","mj":false,"ui":"D051381"},{"d":"Rats, Wistar","mj":false,"ui":"D017208"},{"d":"Sequence Alignment","mj":false,"ui":"D016415"},{"d":"bcl-2-Associated X Protein","mj":false,"qs":[{"q":"chemistry","mj":false,"ui":"Q000737"},{"q":"genetics","mj":false,"ui":"Q000235"},{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D051028"}],"chemicals":[{"n":"3' Untranslated Regions","ui":"D020413","reg":"0"},{"n":"Antagomirs","ui":"D000070416","reg":"0"},{"n":"Antibiotics, Antineoplastic","ui":"D000903","reg":"0"},{"n":"MIRN29 microRNA, rat","ui":"C526366","reg":"0"},{"n":"MicroRNAs","ui":"D035683","reg":"0"},{"n":"Proto-Oncogene Proteins c-bcl-2","ui":"D019253","reg":"0"},{"n":"bcl-2-Associated X Protein","ui":"D051028","reg":"0"},{"n":"Doxorubicin","ui":"D004317","reg":"80168379AG"},{"n":"Caspase 3","ui":"D053148","reg":"EC 3.4.22.-"},{"n":"Caspase 9","ui":"D053453","reg":"EC 3.4.22.-"}],"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":"https://www.karger.com/Article/Pdf/491896","s2_open_access_landing_url":"https://www.semanticscholar.org/paper/c1061aa2b8ca4fc4add037e7318ce44da784f424","s2_open_access_license":"CCBYNCND","s2_open_access_status":"GOLD","pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"Background/Aims: Myocardial apoptosis plays an important role in doxorubicin (Dox) cardiotoxicity. MicroRNA-29 (miR-29) is suggested to function as an anti-fibrotic factor with potential therapeutic effects on cardiac fibrosis. However, it has not been shown whether there is an association between miR-29b and myocardial apoptosis. Methods: Male Wistar rats were transfected with miR-29b agomir by local delivery to the myocardium prior to Dox treatment. Rat cardiomyocytes were pretreated with miR-29b mimics or inhibitor followed by Dox incubation in vitro. Cardiac function and underlying mechanisms were evaluated by echocardiography, immunofluorescence, flow cytometry, real-time PCR, and western blotting. Results: Our results revealed that miR-29b is the only member of the miR-29 family that was significantly downregulated in myocardium from Dox-treated rats. Delivery of miR-29b agomir to myocardium resulted in a marked improvement of cardiac function. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining showed that rescue of miR-29b expression inhibited Dox-induced myocardial apoptosis, concomitantly with increased Bcl-2 expression and decreased Bax expression and caspase-3 activity. In vitro, miR-29b overexpression mitigated, whereas inhibition of miR-29b promoted, Dox-induced cardiomyocyte apoptosis. Mechanistically, miR-29b negatively regulated Bax expression by directly targeting the 3′ untranslated region of Bax. In Dox-treated cardiomyocytes, upregulation of miR-29b resulted in a significant decrease in Bax expression, with an increase in Bcl-2 expression, accompanied by inhibition of mitochondrial membrane depolarization, cytochrome c release, and caspase activation. However, inhibition of miR-29b produced the opposite effects by further augmenting the effects of Dox. Conclusions: These data demonstrate that miR-29b prevents Dox-induced myocardial apoptosis through inhibition of the mitochondria-dependent pathway by directly targeting Bax, suggesting that miR-29b is a potential novel therapeutic target for the treatment of Dox cardiotoxicity.","claims":[{"public_id":"cl_bdf5e5a3891004ea9bdd006f1b776ef7","status":"active","text":"Delivery of a miR-29b agomir to the myocardium markedly improves cardiac function after doxorubicin treatment.","confidence":0.97,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_bdf5e5a3891004ea9bdd006f1b776ef7"},{"public_id":"cl_3708a5864dbfa9fd8468e841c2ac37c3","status":"active","text":"Restoring miR-29b expression inhibits doxorubicin-induced myocardial apoptosis and is accompanied by increased Bcl-2 expression, decreased Bax expression, and reduced caspase-3 activity.","confidence":0.97,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_3708a5864dbfa9fd8468e841c2ac37c3"},{"public_id":"cl_5d274a16325793b16e878864d5562e39","status":"active","text":"miR-29b directly targets the 3′ untranslated region of Bax and suppresses Bax expression, thereby inhibiting the mitochondria-dependent apoptotic pathway.","confidence":0.99,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_5d274a16325793b16e878864d5562e39"},{"public_id":"cl_be036af0ec006e4365d634c36f8ccabe","status":"active","text":"miR-29b is the only member of the miR-29 family that is significantly downregulated in myocardium from doxorubicin-treated rats.","confidence":0.98,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_be036af0ec006e4365d634c36f8ccabe"},{"public_id":"cl_02d302407a0f145333e585ae41fe5ede","status":"active","text":"miR-29b overexpression mitigates doxorubicin-induced cardiomyocyte apoptosis, whereas miR-29b inhibition promotes it in vitro.","confidence":0.96,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_02d302407a0f145333e585ae41fe5ede"}],"concepts":[{"public_id":"co_0fd74cd15e358428c027b5c802af9d48","status":"active","name":"miR-29b agomir","description":"A synthetic miR-29b agonist used for local myocardial delivery to raise miR-29b levels.","types":["oligonucleotide reagent"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_0fd74cd15e358428c027b5c802af9d48"},{"public_id":"co_2ba91bd3d06ec7ff1cc7b789df5c93e9","status":"active","name":"miR-29b","description":"A microRNA in the miR-29 family investigated as a regulator of cardiomyocyte apoptosis.","types":["microRNA"],"aliases":["microRNA-29b"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_2ba91bd3d06ec7ff1cc7b789df5c93e9"},{"public_id":"co_39d4977e840d79dac9b9afa1cca129e0","status":"active","name":"miR-29b mimics","description":"Synthetic molecules used to increase miR-29b activity in cultured cardiomyocytes.","types":["oligonucleotide reagent"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_39d4977e840d79dac9b9afa1cca129e0"},{"public_id":"co_3d3b999684ecbd5c456c9f59d906cd0b","status":"active","name":"mitochondria-dependent apoptotic pathway","description":"The intrinsic apoptosis pathway involving mitochondrial depolarization, cytochrome c release, and caspase activation.","types":["biological pathway"],"aliases":["mitochondria-dependent pathway"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_3d3b999684ecbd5c456c9f59d906cd0b"},{"public_id":"co_557f07c2878028deeccc8ed5e57c1a9c","status":"active","name":"Bcl-2","description":"An anti-apoptotic protein measured as part of the mitochondrial apoptosis pathway.","types":["protein"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_557f07c2878028deeccc8ed5e57c1a9c"},{"public_id":"co_66e7ddec0cf0df45b2e3689b2eef3643","status":"active","name":"myocardial apoptosis","description":"Programmed cell death occurring in heart muscle cells.","types":["cell death process"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_66e7ddec0cf0df45b2e3689b2eef3643"},{"public_id":"co_6b75e59265b6eb5e8fd504d48883bcfc","status":"active","name":"caspase-3","description":"An executioner caspase whose activity reflects apoptosis progression.","types":["protein"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_6b75e59265b6eb5e8fd504d48883bcfc"},{"public_id":"co_9042850d00d1ace7175e4a3bea64b30f","status":"active","name":"myocardium","description":"The heart muscle tissue targeted for local miR-29b delivery and measurement.","types":["tissue"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_9042850d00d1ace7175e4a3bea64b30f"},{"public_id":"co_a16bd9071d32a05df4968440fe4fa5dd","status":"active","name":"miR-29 family","description":"A family of related microRNAs that includes miR-29b.","types":["microRNA family"],"aliases":["microRNA-29 family"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_a16bd9071d32a05df4968440fe4fa5dd"},{"public_id":"co_b68686e2ebe7b3ed6a230a6b992695f0","status":"active","name":"doxorubicin-treated rats","description":"Male Wistar rats exposed to doxorubicin and used as the in vivo cardiotoxicity model.","types":["animal model"],"aliases":["Dox-treated rats"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_b68686e2ebe7b3ed6a230a6b992695f0"},{"public_id":"co_b8ed5d34ba64e9e4983c63bd0bcbc0f3","status":"active","name":"doxorubicin-induced cardiomyocyte apoptosis","description":"Apoptotic death of cultured heart muscle cells after doxorubicin exposure.","types":["cell death process"],"aliases":["Dox-induced cardiomyocyte apoptosis"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_b8ed5d34ba64e9e4983c63bd0bcbc0f3"},{"public_id":"co_c9df888533d8ebe392cc1c9e1f9ef526","status":"active","name":"3′ untranslated region","description":"The non-coding region of Bax mRNA that was directly bound by miR-29b.","types":["RNA region"],"aliases":["3′ UTR"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_c9df888533d8ebe392cc1c9e1f9ef526"},{"public_id":"co_def72bbd4a00222d50c0935961284098","status":"active","name":"Bax","description":"A pro-apoptotic Bcl-2 family protein targeted by miR-29b in the study.","types":["protein"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_def72bbd4a00222d50c0935961284098"},{"public_id":"co_e981777db1bad9d9da8e96e74306961e","status":"active","name":"miR-29b inhibitor","description":"A reagent used to suppress miR-29b activity in cultured cardiomyocytes.","types":["oligonucleotide reagent"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_e981777db1bad9d9da8e96e74306961e"},{"public_id":"co_f1108f25e52790aced4405b9b2519a43","status":"active","name":"cardiac function","description":"The functional performance of the heart as assessed by echocardiography in the rat model.","types":["outcome"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_f1108f25e52790aced4405b9b2519a43"}],"external_ids":{"DOI":"10.1159/000491896","ArXiv":null,"PubMed":30025410,"PubMedCentral":null,"MAG":2883087878,"DBLP":null,"ACL":null},"open_access":{"is_open_access":true,"pdf_url":"https://www.karger.com/Article/Pdf/491896","landing_url":"https://www.semanticscholar.org/paper/c1061aa2b8ca4fc4add037e7318ce44da784f424","source":"semantic_scholar","pdf_url_source":"semantic_scholar_open_access_pdf","license":"CCBYNCND","status":"GOLD","reason":null},"reference_availability":{"status":"available","references_indexed":true,"full_text_available":false,"full_text_source":null,"count_basis":"semantic_scholar_metadata","extraction_status":"not_applicable","reason":null},"source":{"provider":"episteme2","base_corpus":"semantic_scholar_dump","freshness_mode":"unknown","basis":["semantic_scholar_metadata","postgres_metadata"],"limits":["paper metadata is based on indexed upstream scholarly datasets","claims and concepts are available only for extracted papers","absence of claims or concepts means no extracted graph data is available in this response"],"status":"available","degraded":false,"degraded_reasons":[],"diagnostics":{"status":"available","degraded":false,"degraded_reasons":[],"metadata_status":"available","graph_status":"available","abstract_status":"available"},"source_flags":5},"paper_id":632077,"paper_uid":"a47a7ed9-71b0-4ef5-b2a6-5a54fa898fa0","canonical_identity":{"paper_id":632077,"paper_uid":"a47a7ed9-71b0-4ef5-b2a6-5a54fa898fa0","identity_status":"available","lookup_basis":"semantic_scholar_external_id","compatibility_path":"corpus_id"},"url":"https://sah.borca.ai/papers/51702450"}