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This makes the elucidation of disease mechanisms and the identification of novel potential therapeutic targets a priority. Here, we performed RNA sequencing on ventricular myocardial biopsies from patients with HFpEF, prospecting to discover distinctive transcriptomic signatures. A total of 306 differentially expressed mRNAs (DEG) and 152 differentially expressed microRNAs (DEM) were identified and enriched in several biological processes involved in HF. Moreover, by integrating mRNA and microRNA expression data, we identified five potentially novel miRNA\u2013mRNA relationships in HFpEF: the upregulated hsa-miR-25-3p, hsa-miR-26a-5p, and has-miR4429, targeting HAPLN1; and NPPB mRNA, targeted by hsa-miR-26a-5p and miR-140-3p. Exploring the predicted miRNA\u2013mRNA interactions experimentally, we demonstrated that overexpression of the distinct miRNAs leads to the downregulation of their target genes. Interestingly, we also observed that microRNA signatures display a higher discriminative power to distinguish HFpEF sub-groups over mRNA signatures. Our results offer new mechanistic clues, which can potentially translate into new HFpEF therapies.<\/jats:p>","DOI":"10.3390\/biomedicines11082131","type":"journal-article","created":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T07:35:24Z","timestamp":1690529724000},"page":"2131","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Myocardial RNA Sequencing Reveals New Potential Therapeutic Targets in Heart Failure with Preserved Ejection Fraction"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9790-8335","authenticated-orcid":false,"given":"Jos\u00e9 M.","family":"In\u00e1cio","sequence":"first","affiliation":[{"name":"Stem Cells and Development Laboratory, iNOVA4Health, NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal"}]},{"given":"Fernando","family":"Cristo","sequence":"additional","affiliation":[{"name":"Stem Cells and Development Laboratory, iNOVA4Health, NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6601-7513","authenticated-orcid":false,"given":"Miguel","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"Genome Medicine Lab, Department of Medical Sciences, Institute for Biomedicine\u2014iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"given":"Francisco","family":"Vasques-N\u00f3voa","sequence":"additional","affiliation":[{"name":"Cardiovascular R&D Centre\u2014UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, 1169-056 Porto, Portugal"}]},{"given":"Francisca","family":"Saraiva","sequence":"additional","affiliation":[{"name":"Cardiovascular R&D Centre\u2014UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, 1169-056 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8961-3097","authenticated-orcid":false,"given":"Mafalda M.","family":"Nunes","sequence":"additional","affiliation":[{"name":"Stem Cells and Development Laboratory, iNOVA4Health, NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal"}]},{"given":"Gra\u00e7a","family":"Rosas","sequence":"additional","affiliation":[{"name":"Stem Cells and Development Laboratory, iNOVA4Health, NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal"}]},{"given":"Andreia","family":"Reis","sequence":"additional","affiliation":[{"name":"Genome Medicine Lab, Department of Medical Sciences, Institute for Biomedicine\u2014iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"given":"Rita","family":"Coimbra","sequence":"additional","affiliation":[{"name":"Genome Medicine Lab, Department of Medical Sciences, Institute for Biomedicine\u2014iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6672-6176","authenticated-orcid":false,"given":"Jos\u00e9 Lu\u00eds","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Institute of Electronics and Informatics Engineering of Aveiro (IEETA), University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2243-6123","authenticated-orcid":false,"given":"Gabriela","family":"Moura","sequence":"additional","affiliation":[{"name":"Genome Medicine Lab, Department of Medical Sciences, Institute for Biomedicine\u2014iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7808-3596","authenticated-orcid":false,"given":"Adelino","family":"Leite-Moreira","sequence":"additional","affiliation":[{"name":"Cardiovascular R&D Centre\u2014UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, 1169-056 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7384-0949","authenticated-orcid":false,"given":"Jos\u00e9 Ant\u00f3nio","family":"Belo","sequence":"additional","affiliation":[{"name":"Stem Cells and Development Laboratory, iNOVA4Health, NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1002\/ejhf.1858","article-title":"Epidemiology of heart failure","volume":"22","author":"Groenewegen","year":"2020","journal-title":"Eur. 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