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. Novelty and SignificanceO_ST_ABSWhat is known?C_ST_ABS*The microRNA-200 (miR-200) family targets several heart factors in vitro. *miR-200c inhibition was shown to protect cardiomyocytes in a myocardial ischemia-reperfusion injury, myocardial cellular model. *miR-200 may play a role in cardiovascular fibrosis, however there are no in vivo reports of the role miR-200 plays in heart repair. What New Information Does This Article Contribute?*PMIS-miR-200c transgenic mice reveal a role for miR-200c inhibition in rapid repair of the heart after a myocardial infarct (MI). After an MI, miR-200c expression increases, to levels observed during early heart development. *Inhibition of miR-200c allows for expression of Tbx5, Gata4, Pitx2, Mef2c, Yap, Nppa and Sox5 factors to repair the heart after ischemic injury. *PMIS-miR-200c mice have increased cardiomyocyte proliferation and reduced cardiac fibroblasts resulting in decreased fibrosis. *Heart function in PMIS-miR-200c mice is significantly restored 3-weeks post-MI. While microRNAs have been extensively studied in heart development and ischemic injury, little is known about the miR-200 family in the cardiovascular system. In other cell types and systems, miR-200 is upregulated under oxidative stress and hypoxia. miR-200c targets Zeb1, eNOS, Sirt1 and Fox01 to regulate cell growth and arrest, apoptosis and senescence in other tissues. miR-200 members are increased in response to ischemia, but this has not been evaluated in the heart. We show a direct effect of miR-200c inhibition and decreased fibrosis in the MI heart. The miR-200 family targets stem cell factors such as Sox2, Klf4, and Bmi1 and our recent sn-RNA multiomics analyses of PMIS-miR-200c mice revealed de-differentiated or immature cardiomyocytes. Thus, inhibition of miR-200c reactivates transcription factors after an MI, important for cardiomyocyte renewal. This research demonstrates how inhibition of miR-200 regulates cardiac function after an MI.