Activation of developmental transcription factors using RNA technology promotes heart repair

Ischemic injury and adverse post-infarction myocardial remodeling are major causes of heart failure. We previously reported that microRNA (miR)-200c inhibition in murine embryos increased cardiogenic transcription factors (TFs) Tbx5, Gata4, and Mef2c to activate an immature cardiomyocyte cell state, suggesting miR-200 inhibition as a therapy for cardiac repair. We performed permanent ligation of the left anterior descending artery (a severe myocardial infarct, MI) on PMIS-miR-200c (inhibition of miR-200c; PMIS-C), PMIS-A (inhibition of miR-200a) and wildtype adult mice. Echocardiographic left ventricular (LV) ejection fraction (EF) at 3 WPI (weeks post-injury) was 22% ± 4.31% (WT) but increased to 56% ± 4.25% (PMIS-C) (p ≤ 0.0001). Post-infarction LV chamber dilation was reversed in PMIS-C mice compared to WT, and trichrome staining showed a decrease in fibrosis 3 WPI. By 9 WPI, PMIS-C heart function was like that of WT mice before injury. Tbx5, Gata4, Mef2c, and Isl-1 were increased after MI in PMIS-C hearts. PMIS-C mice recover cardiac function and reverse ischemic pathology of acute cardiac injury in adult mice. Inhibition of miR-200c activates several important pathways in heart development and repair mechanisms after an MI in adult hearts. The PMIS-miR-200c transgenic mice demonstrate an important role for miR-200c in regulating heart repair after ischemic injury.