Cardiac protection induced by urocortin-2 enables the regulation of apoptosis and fibrosis after ischemia and reperfusion involving miR-29a modulation
Calderón Sánchez, Eva M.
Martín Bórnez, Marta
Gutierrez Carretero, Encarnacion
Fernández Velasco, María
Ordóñez Fernández, José Antonio
Smani Hajami, Tarik
|Department||Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica
Universidad de Sevilla. Departamento de Cirugía
|Abstract||Urocortin-2 (Ucn-2) has demonstrated cardioprotective ac tions against myocardial ischemia-reperfusion (I/R) injuries.
Herein, we explored the protective role of Ucn-2 through
microRNAs (miRNAs) post-transcriptional ...
Urocortin-2 (Ucn-2) has demonstrated cardioprotective ac tions 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 upregula tion 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. Inter estingly, a significant upregulation of Hmox-1 was observed in the ventricle of ischemic patients with heart failure, corre lating 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.
|Citation||Mayoral-González, I., Calderón Sánchez, E.M., Galeano-Otero, I., Martín Bórnez, M., Gutierrez Carretero, E., Fernández Velasco, M.,...,Smani Hajami, T. (2022). Cardiac protection induced by urocortin-2 enables the regulation of apoptosis and fibrosis after ischemia and reperfusion involving miR-29a modulation. Molecular Therapy-Nucleic Acids, 27, 838-853. https://doi.org/10.1016/j.omtn.2022.01.003.|