DILATED CARDIOMYOPATHY RODENT MODEL GENERATED BY TTN GENE MODULTAION

Abstract

TTN truncating variants (TTNtv) account for the largest proportion of dilated cardiomyopathy (DCM) patients in the clinic. TTN insufficiency caused by TTNtv is generally considered as the molecular mechanism. Here, we reported that an effective DCM mouse model could be generated with overt symptoms within a short period by reducing 50% of Ttn via adeno-associated virus-mediated Ttn shRNA. Moreover, a transcription factor, Yin Yang 1 (Yy1), could significantly attenuate DCM symptoms and. Yy1 therapy could increase the expression of Ccnd1 and Ccnd2, promoting more cardiomyocytes overriding S phase. In addition, overexpressing either Ccnd1 or Ccnd2 was therapeutic, and the beneficial function of Yy1 could be outstandingly compromised by blocking both Ccnd1 and Ccnd2. In conclusion, the therapeutic mechanisms of Yy1 treatment could be multiple, and cardiac cell cycle re-entry was validated to be the primary one.