Hinders Cardiac Healing by Suppressing ZEB2 Reactivation and Cardiomyocyte Dedifferentiation.

Abstract

BACKGROUND: Long noncoding RNAs (lncRNA) have emerged as critical regulators in cardiovascular biology, influencing cardiac development, remodeling, and regeneration.(zeb2 opposite strand), a natural antisense transcript of the(zinc finger E-box-binding homeobox 2) gene, has been linked to these processes in various organs. Although ZEB2 promotes cardiac repair, the rolein these processes remains unclear. This study investigates the role ofin modulating ZEB2 expression and cardiac remodeling after ischemic injury. METHODS: We used adeno-associated virus vectors to overexpressin mouse models of cardiac IR (ischemia/reperfusion) injury. RNA sequencing, immunofluorescence, and high-resolution respirometry were used to evaluate the effects ofdelivery on gene expression, ZEB2 reactivation, cardiomyocyte phenotype, scar composition, and mitochondrial function. Experiments in cultured cardiomyocytes under hypoxia further explored the regulatory dynamics betweenand. RESULTS: We identifiedas a hypoxia-responsive lncRNA that displays an inverse and oscillatory expression pattern within both in vitro and in vivo models of cardiac injury. Functional experiments revealed thatnegatively regulates ZEB2 expression, impairing the cardiomyocyte dedifferentiation and metabolic remodeling necessary for effective repair. Adeno-associated virus-mediated delivery ofresulted in preserved sarcomere structure, altered scar composition, reduced expression of regenerative genes, and diminished cardiac function following injury. In contrast, silencing ofincreased ZEB2 protein expression, suggesting a potential therapeutic strategy to enhance repair. Mechanistically, modulation oflevels inversely regulated ZEB2 protein expression, whereas ZEB2 modulation did not affectlevels, indicating a unidirectional regulatory axis between the 2 transcripts. CONCLUSIONS: Our findings identifyas a stress-responsive inhibitor of ZEB2 reactivation that limits cardiomyocyte plasticity and hinders repair following ischemic injury. Given its specific activity under ischemic conditions, targetingmay represent a novel therapeutic strategy to enhance endogenous cardiac regeneration.