Mayoral-Gonzalez, IsabelCalderon-Sanchez, Eva MGaleano-Otero, IsabelMartin-Bornez, MartaGutierrez-Carretero, EncarnacionFernandez-Velasco, MariaDomenech, NievesCrespo-Leiro, Maria GenerosaGomez, Ana MariaOrdoñez-Fernandez, AntonioHmadcha, AbdelkrimSmani, Tarik2023-05-032023-05-032022-01-10Mayoral-González I, Calderón-Sánchez EM, Galeano-Otero I, Martín-Bórnez M, Gutiérrez-Carretero E, Fernández-Velasco M, et al. Cardiac protection induced by urocortin-2 enables the regulation of apoptosis and fibrosis after ischemia and reperfusion involving miR-29a modulation. Mol Ther Nucleic Acids. 2022 Jan 10;27:838-853.2162-2531http://hdl.handle.net/10668/22458Urocortin-2 (Ucn-2) has demonstrated cardioprotective actions against myocardial ischemia-reperfusion (I/R) injuries. Herein, we explored the protective role of Ucn-2 through microRNAs (miRNAs) post-transcriptional regulation of apoptotic and pro-fibrotic genes. We determined that the intravenous administration of Ucn-2 before heart reperfusion in a Wistar rat model of I/R recovered cardiac contractility and decreased fibrosis, lactate dehydrogenase release, and apoptosis. The infusion of Ucn-2 also inhibited the upregulation of 6 miRNAs in revascularized heart. The in silico analysis indicated that miR-29a and miR-451_1∗ are predicted to target many apoptotic and fibrotic genes. Accordingly, the transfection of neonatal rat ventricular myocytes with mimics overexpressing miR-29a, but not miR-451_1∗, prevented I/R-induced expression of pro- and anti-apoptotic genes such as Apaf-1, Hmox-1, and Cycs, as well as pro-fibrotic genes Col-I and Col-III. We also confirmed that Hmox-1, target of miR-29a, is highly expressed at the mRNA and protein levels in adult rat heart under I/R, whereas, Ucn-2 abolished I/R-induced mRNA and protein upregulation of HMOX-1. Interestingly, a significant upregulation of Hmox-1 was observed in the ventricle of ischemic patients with heart failure, correlating negatively with the left ventricle ejection fraction. Altogether, these data indicate that Ucn-2, through miR-29a regulation, provides long-lasting cardioprotection, involving the post-transcriptional regulation of apoptotic and fibrotic genes.enAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Ucn-2apoptosiscardiac remodelingfibrosisheart failureischemia and reperfusionmiRNAMicroRNAsMyocardial Reperfusion InjuryUrocortinsUp-RegulationL-Lactate DehydrogenaseMyocytes, CardiacFibrosisReperfusionresearch article35141045open accessGenesRegulación hacia arribaCorazónARN MensajeroProteínasReperfusiónCélulas muscularesUrocortinasIsquemia MiocárdicaInsuficiencia Cardíaca10.1016/j.omtn.2022.01.003PMC8807986http://www.cell.com/article/S2162253122000087/pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807986/pdf