Author(s):
Inácio, José M. ; Cristo, Fernando ; Pinheiro, Miguel ; Vasques-Nóvoa, Francisco ; Saraiva, Francisca ; Nunes, Mafalda M. ; Rosas, Graça ; Reis, Andreia ; Coimbra, Rita ; Oliveira, José Luís ; Moura, Gabriela ; Leite-Moreira, Adelino ; Belo, José A.
Date: 2023
Persistent ID: http://hdl.handle.net/10362/157766
Origin: Repositório Institucional da UNL
Subject(s): heart failure; HFpEF; intercellular communication; miRNA signature in HFpEF; miRNA–mRNA; Medicine (miscellaneous); Biochemistry, Genetics and Molecular Biology(all)
Description
Funding Information: This work was supported by the Fundação para a Ciência e a Tecnologia (NETDIAMOND-SAICTPAC/0047/2015), Scientific Employment Stimulus to J.M.I. (Norma Transitória 8189/2018), post-doctoral fellowship to F.C. (DAI/2019/08/SAICTPAC/0047/2015), iNOVA4Health-UID/Multi/04462/2020 and LS4FUTURE Associated Laboratory (LA/P/0087/2020). Genome Medicine Lab is funded by FCT and COMPETE2020 (iBiMED: UID/BIM/04501/2020; GenomePT: POCI-01-0145-FEDER-022184). Within the scope of the Cardiovascular R&D Center, this work was financed by national funds through FCT (UIDB/00051/2020 and UIDP/00051/2020) and RISE (LA/P/0053/2020). Publisher Copyright: © 2023 by the authors.
Heart failure with preserved ejection fraction (HFpEF) represents a global health challenge, with limited therapies proven to enhance patient outcomes. 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–mRNA 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–mRNA 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.
