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Notably, circRNAs can interact with miRNAs, influencing their specific mRNA targets\u2019 levels and shaping a competing endogenous RNAs (ceRNA) network. However, these interactions and their respective functions remain largely unexplored in ischemic heart failure (IHF). This study is aimed at identifying circRNA-centered ceRNA networks in non-end-stage IHF. Approximately 662 circRNA-miRNA-mRNA interactions were identified in the heart by combining state-of-the-art bioinformatics tools with experimental data. Importantly, KEGG terms of the enriched mRNA indicated CVD-related signaling pathways. A specific network centered on circBPTF was validated experimentally. The levels of let-7a-5p, miR-18a-3p, miR-146b-5p, and miR-196b-5p were enriched in circBPTF pull-down experiments, and circBPTF silencing inhibited the expression of HDAC9 and LRRC17, which are targets of miR-196b-5p. Furthermore, as suggested by the enriched pathway terms of the circBPTF ceRNA network, circBPTF inhibition elicited endothelial cell cycle arrest. circBPTF expression increased in endothelial cells exposed to hypoxia, and its upregulation was confirmed in cardiac samples of 36 end-stage IHF patients compared to healthy controls. In conclusion, circRNAs act as miRNA sponges, regulating the functions of multiple mRNA targets, thus providing a novel vision of HF pathogenesis and laying the theoretical foundation for further experimental studies.<\/jats:p>","DOI":"10.3390\/cells12212578","type":"journal-article","created":{"date-parts":[[2023,11,5]],"date-time":"2023-11-05T07:35:06Z","timestamp":1699169706000},"page":"2578","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["circRNA-miRNA-mRNA Deregulated Network in Ischemic Heart Failure Patients"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7854-8381","authenticated-orcid":false,"given":"Alisia","family":"Mad\u00e8","sequence":"first","affiliation":[{"name":"Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Bibi","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"},{"name":"Department of Biosciences, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Manuel","family":"Garcia-Manteiga","sequence":"additional","affiliation":[{"name":"Center for Omics Sciences COSR, BioInformatics Laboratory, San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Sofia","family":"Tascini","sequence":"additional","affiliation":[{"name":"Center for Omics Sciences COSR, BioInformatics Laboratory, San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Universit\u00e0 Vita-Salute San Raffaele, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago Nicolas","family":"Piella","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Tikhomirov","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0824-060X","authenticated-orcid":false,"given":"Christine","family":"Voellenkle","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Gaetano","sequence":"additional","affiliation":[{"name":"Laboratory of Epigenetics, Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Przemyslaw","family":"Leszek","sequence":"additional","affiliation":[{"name":"Department of Heart Failure and Transplantology, National Institute of Cardiology, 04-628 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5365-7063","authenticated-orcid":false,"given":"Serenella","family":"Castelvecchio","sequence":"additional","affiliation":[{"name":"Department of Adult Cardiac Surgery, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8530-6284","authenticated-orcid":false,"given":"Lorenzo","family":"Menicanti","sequence":"additional","affiliation":[{"name":"Department of Adult Cardiac Surgery, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8624-7738","authenticated-orcid":false,"given":"Fabio","family":"Martelli","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0275-7221","authenticated-orcid":false,"given":"Simona","family":"Greco","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1038\/sj.ejhg.5201459","article-title":"The Amazing Complexity of the Human Transcriptome","volume":"13","author":"Frith","year":"2005","journal-title":"Eur. 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