Cardiomyocyte-Specific LncRNA CSTPP Prolongs the Proliferation Window by Promoting CDKN1A Decay in Postinfarction Cardiac Regeneration

BACKGROUND: Adult mammalian cardiomyocytes exhibit some capacity to reenter the cell cycle after ischemic injury. However, activated cardiomyocytes rapidly undergo cell cycle rearrest shortly after activation. Long noncoding RNAs (lncRNAs) have emerged as critical regulators of cardiac regeneration; however, their involvement in the process of cell cycle rearrest remains unexplored. METHODS: Bulk RNA-sequencing was used to screen for lncRNAs differentially expressed during myocardial injury. Loss- and gain-of-function approaches were used to assess the role of lncRNA in cardiomyocyte proliferation and cardiac regeneration after myocardial infarction (MI). RNA pulldown and RNA immunoprecipitation were used to elucidate the underlying regulatory mechanisms. RESULTS: We identified a cardiomyocyte-specific lncRNA downregulated after myocardial injury and named it cardiomyocyte-specific transcript promoting proliferation (CSTPP). CSTPP overexpression enhanced neonatal rat ventricular myocyte proliferation, whereas its knockdown exerted the opposite effects. In vivo, CSTPP deletion attenuated cardiomyocyte proliferation, leading to exacerbated cardiac dysfunction post-MI. Conversely, CSTPP overexpression promoted cardiomyocyte proliferation and improved cardiac function. Furthermore, CDKN1A (cyclin-dependent kinase inhibitor 1A) was found to be upregulated in cardiomyocytes localized at the border zone after MI, which was aggravated by CSTPP knockout and abrogated by CSTPP overexpression. Mechanistically, we showed that CSTPP interacts with YBX1 (Y box–binding protein 1), reinforcing the interaction between YBX1 and UPF1 (upstream frameshift 1), thereby enhancing UPF1 recruitment to CDKN1A mRNA and accelerating its decay. Notably, CSTPP was downregulated in heart samples from patients with MI. CSTPP overexpression decreased CDKN1A expression and facilitated proliferation in human induced pluripotent stem cell–derived cardiomyocytes. CONCLUSIONS: Our findings identified CSTPP as a cardiomyocyte-specific lncRNA that functions to extend the activation window of the cardiomyocyte cell cycle after MI by stabilizing the YBX1-UPF1 interaction and thus facilitating the UPF1-mediated decay of CDKN1A mRNA. These results establish CSTPP as a promising therapeutic target for cardiac regeneration after MI.