Yasutomi Higashikuni, Colin Platt, Margaret H Hastings, William C W Chen, Justin R B Guerra, Takeshi Tokuyama, Fuad Gandhi Torizal, Wenhao Liu, Takumi Obana, Abraham L Bayer, Hannah Whipple, Alexandra Kuznetsov, Ashish Yeri, Cole Turissini, Robert R Kitchen, Kota Shibayama, Takayoshi Matsumura, Norihiko Takeda, Hideki Uosaki, Aarti H Asnani, Timothy K Lu, Anthony Rosenzweig
{"title":"使用组合遗传学集体（CombiGEM）鉴定的协同miRNA组合减轻阿霉素心脏毒性","authors":"Yasutomi Higashikuni, Colin Platt, Margaret H Hastings, William C W Chen, Justin R B Guerra, Takeshi Tokuyama, Fuad Gandhi Torizal, Wenhao Liu, Takumi Obana, Abraham L Bayer, Hannah Whipple, Alexandra Kuznetsov, Ashish Yeri, Cole Turissini, Robert R Kitchen, Kota Shibayama, Takayoshi Matsumura, Norihiko Takeda, Hideki Uosaki, Aarti H Asnani, Timothy K Lu, Anthony Rosenzweig","doi":"10.1016/j.jaccao.2025.03.007","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Cardiomyocyte loss occurs in acute and chronic cardiac injury, including cardiotoxicity due to chemotherapeutics like doxorubicin, and contributes to heart failure development. There is a pressing need for cardiac-specific therapeutics that target cardiomyocyte loss, preventing chemotherapy complications without compromising chemotherapeutic efficacy.</p><p><strong>Objectives: </strong>The authors employed massively parallel combinatorial genetic screening to find microRNA (miRNA) combinations that promote cardiomyocyte survival.</p><p><strong>Methods: </strong>CombiGEM (combinatorial genetics en masse) screening in a cardiomyocyte cell line was followed by validation in the original cell type and screening in primary cardiomyocytes. The top combination was tested in mouse and developing zebrafish models of doxorubicin cardiotoxicity. RNA sequencing provided insight into possible mechanisms.</p><p><strong>Results: </strong>Multiple miRNA combinations protected cardiomyocytes from doxorubicin in vitro. The most effective (miR-222+miR-455) appeared to act synergistically, and mitigated doxorubicin cardiotoxicity phenotypes in murine and zebrafish in vivo models. RNA sequencing revealed overlapping and synergistic regulation of relevant genes and biological processes in cardiomyocytes, including mitochondrial homeostasis, oxidative stress, muscle contraction, and others.</p><p><strong>Conclusions: </strong>We identified miR-222 and miR-455 as a combination with potential therapeutic applications for cardioprotection. This study furthers our knowledge of the cardiac effects of miRNAs and their combinations and demonstrates the potential of CombiGEM for cardioprotective combinatorial therapeutic discovery.</p>","PeriodicalId":48499,"journal":{"name":"Jacc: Cardiooncology","volume":" ","pages":""},"PeriodicalIF":12.0000,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Mitigation of Doxorubicin Cardiotoxicity With Synergistic miRNA Combinations Identified Using Combinatorial Genetics en masse (CombiGEM).\",\"authors\":\"Yasutomi Higashikuni, Colin Platt, Margaret H Hastings, William C W Chen, Justin R B Guerra, Takeshi Tokuyama, Fuad Gandhi Torizal, Wenhao Liu, Takumi Obana, Abraham L Bayer, Hannah Whipple, Alexandra Kuznetsov, Ashish Yeri, Cole Turissini, Robert R Kitchen, Kota Shibayama, Takayoshi Matsumura, Norihiko Takeda, Hideki Uosaki, Aarti H Asnani, Timothy K Lu, Anthony Rosenzweig\",\"doi\":\"10.1016/j.jaccao.2025.03.007\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Cardiomyocyte loss occurs in acute and chronic cardiac injury, including cardiotoxicity due to chemotherapeutics like doxorubicin, and contributes to heart failure development. There is a pressing need for cardiac-specific therapeutics that target cardiomyocyte loss, preventing chemotherapy complications without compromising chemotherapeutic efficacy.</p><p><strong>Objectives: </strong>The authors employed massively parallel combinatorial genetic screening to find microRNA (miRNA) combinations that promote cardiomyocyte survival.</p><p><strong>Methods: </strong>CombiGEM (combinatorial genetics en masse) screening in a cardiomyocyte cell line was followed by validation in the original cell type and screening in primary cardiomyocytes. The top combination was tested in mouse and developing zebrafish models of doxorubicin cardiotoxicity. RNA sequencing provided insight into possible mechanisms.</p><p><strong>Results: </strong>Multiple miRNA combinations protected cardiomyocytes from doxorubicin in vitro. The most effective (miR-222+miR-455) appeared to act synergistically, and mitigated doxorubicin cardiotoxicity phenotypes in murine and zebrafish in vivo models. RNA sequencing revealed overlapping and synergistic regulation of relevant genes and biological processes in cardiomyocytes, including mitochondrial homeostasis, oxidative stress, muscle contraction, and others.</p><p><strong>Conclusions: </strong>We identified miR-222 and miR-455 as a combination with potential therapeutic applications for cardioprotection. This study furthers our knowledge of the cardiac effects of miRNAs and their combinations and demonstrates the potential of CombiGEM for cardioprotective combinatorial therapeutic discovery.</p>\",\"PeriodicalId\":48499,\"journal\":{\"name\":\"Jacc: Cardiooncology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":12.0000,\"publicationDate\":\"2025-05-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Jacc: Cardiooncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jaccao.2025.03.007\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Jacc: Cardiooncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jaccao.2025.03.007","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
Mitigation of Doxorubicin Cardiotoxicity With Synergistic miRNA Combinations Identified Using Combinatorial Genetics en masse (CombiGEM).
Background: Cardiomyocyte loss occurs in acute and chronic cardiac injury, including cardiotoxicity due to chemotherapeutics like doxorubicin, and contributes to heart failure development. There is a pressing need for cardiac-specific therapeutics that target cardiomyocyte loss, preventing chemotherapy complications without compromising chemotherapeutic efficacy.
Objectives: The authors employed massively parallel combinatorial genetic screening to find microRNA (miRNA) combinations that promote cardiomyocyte survival.
Methods: CombiGEM (combinatorial genetics en masse) screening in a cardiomyocyte cell line was followed by validation in the original cell type and screening in primary cardiomyocytes. The top combination was tested in mouse and developing zebrafish models of doxorubicin cardiotoxicity. RNA sequencing provided insight into possible mechanisms.
Results: Multiple miRNA combinations protected cardiomyocytes from doxorubicin in vitro. The most effective (miR-222+miR-455) appeared to act synergistically, and mitigated doxorubicin cardiotoxicity phenotypes in murine and zebrafish in vivo models. RNA sequencing revealed overlapping and synergistic regulation of relevant genes and biological processes in cardiomyocytes, including mitochondrial homeostasis, oxidative stress, muscle contraction, and others.
Conclusions: We identified miR-222 and miR-455 as a combination with potential therapeutic applications for cardioprotection. This study furthers our knowledge of the cardiac effects of miRNAs and their combinations and demonstrates the potential of CombiGEM for cardioprotective combinatorial therapeutic discovery.
期刊介绍：
JACC: CardioOncology is a specialized journal that belongs to the esteemed Journal of the American College of Cardiology (JACC) family. Its purpose is to enhance cardiovascular care for cancer patients by publishing high-quality, innovative scientific research and sharing evidence-based knowledge.
The journal aims to revolutionize the field of cardio-oncology and actively involve and educate professionals in both cardiovascular and oncology fields. It covers a wide range of topics including pre-clinical, translational, and clinical research, as well as best practices in cardio-oncology. Key areas of focus include understanding disease mechanisms, utilizing in vitro and in vivo models, exploring novel and traditional therapeutics (across Phase I-IV trials), studying epidemiology, employing precision medicine, and investigating primary and secondary prevention.
Amyloidosis, cardiovascular risk factors, heart failure, and vascular disease are some examples of the disease states that are of particular interest to the journal. However, it welcomes research on other relevant conditions as well.
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