Abstract Body: Background: Circular RNAs (circRNAs) are emerging as potential biomarkers and therapeutic targets, yet their roles in cardiac regeneration and myocardial renewal remain largely unexplored.
Hypothesis: CircIGF1R plays a crucial role in cardiac regeneration by modulating the proliferation and survival of cardiomyocytes post ischemic insults via circIGF1R/DDX5/β-catenin axis.
Aims: This study aimed to delineate circIGF1R's roles in cardiac regeneration and identify new therapeutic strategies for myocardial repair.
Methods: Circular RNA profiling was conducted using genome-wide RNA sequencing data from neonatal and adult primary cardiomyocytes, and from sham and myocardial infarction (MI) neonatal mice hearts. Ten circRNAs associated with regeneration were identified, including circIGF1R. Myocardial circRNA expression was assessed by qPCR and in situ hybridization. Gain- and loss-of-function experiments in vitro and in vivo were performed to evaluate the role of the identified circRNA in cardiac regeneration post ischemic injury. RNA pull-down and RIP assays were used to identify circRNA-protein interactions, complemented by coimmunoprecipitation Co-IP assays for protein-protein interaction analysis.
Results: CircIGF1R expression was high in neonatal hearts, decreased with postnatal maturation, and upregulated post apical resection (AR) in mice, and in patients with acute myocardial infarction (AMI) diagnosed within one week. In hiPSC-CMs and in myocardial tissue from mice post-AR and MI, we observed that circIGF1R overexpression enhanced cardiomyocyte proliferation, reduced apoptosis, and mitigated cardiac dysfunction and fibrosis. CircIGF1R knockdown impeded endogenous cardiac renewal. Mechanistically, circIGF1R directly bound to DDX5, augmenting its protein levels. This subsequently enhanced the interaction between DDX5 and β-catenin, thereby promoting nuclear localization of β-catenin and transcriptionally activating c-Myc and cyclin D1 to foster cardiac regeneration and myocardial repair.
Conclusions: Our findings highlight the pivotal role of circIGF1R in facilitating cardiac regeneration and repair post ischemic insults. The circIGF1R/DDX5/β-catenin axis emerges as a novel therapeutic target for enhancing myocardial repair post-MI, offering promising avenues for the development of regenerative therapies.