Abstract 19: Microrna-19b Enhances Cardiac Cell Survival After Ischemic Injury
Ischemia/reperfusion (I/R) injury in cardiac tissue results in substantial loss of cardiomyocytes, leading to a functional decline. The release of several cytokines increases cardiomyocyte survival after ischemic injury by activating the janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway. However, this pathway is inhibited by Suppressor of cytokine signaling (SOCS)1 and SOCS3, which act as endogenous negative regulators of cardiomyocyte survival by blocking JAK activity.
MicroRNAs (miRNAs) are small, non-coding RNAs that can repress gene expression by binding to recognition sequences within target genes. In a bioinformatic screen, we identified conserved binding sites in SOCS1 and 3 for miR-19b. Using a luciferase reporter assay, we were able to confirm direct binding of miR-19b to the 3’-UTR of both SOCS1 and 3 in vitro. In addition, we found that miR-19b downregulates SOCS1 in cardiac-like cells and isolated neonatal cardiomyocytes. In vivo, we observed a downregulation of miR-19b in both rodent and human cardiac tissues after ischemic injury, which corresponds to an upregulation of both SOCS1 and 3.
Since inhibition of SOCS1 and 3 could enhance cardiac JAK-STAT signaling, miRNA-based inhibition could lead to an increase in cardiomyocyte survival. Here we show that cardiomyocyte-specific overexpression of miR-19b lowers SOCS1 and SOCS3 expression and enhances JAK-STAT signaling during ischemia reperfusion, which corresponds to a decrease in the pro-apoptotic proteins Bad, Bax and P53. Additional genes that are decreased by miR-19b during ischemic injury are Rnf11 and TNFAIP3, both repressors NF-kB signaling. To further explore the cardioprotective effects of miR-19b, we are currently investigating the therapeutic benefits of administering synthetic miR-19b mimics through intracardiac injection after I/R injury in mice.
Our study indicates a conserved mechanism by which miR-19b targets both SOCS1 and 3 and to increase the activation of JAK/STAT signaling to decrease cardiomyocyte apoptosis. Administration of miR-19b mimics might be of therapeutic interest to enhance cardiomyocyte cells survival and preserve heart function in the setting of ischemic injury.
Author Disclosures: B. Molenaar: None. C. Demkes: None. H. Ruiter, de: None. D. Versteeg: None. M. Gladka-de Vries: None. R. Korporaal: None. E. Deel, van: None. H.M. Semus: None. E. van Rooij: None.
- © 2015 by American Heart Association, Inc.