Extracellular vesicle-derived circCEBPZOS attenuates postmyocardial infarction remodeling by promoting angiogenesis via the miR-1178-3p/PDPK1 axis

Emerging studies indicate that extracellular vesicles (EVs) and their inner circular RNAs (circRNAs), play key roles in the gene regulatory network and cardiovascular repair. However, our understanding of EV-derived circRNAs in cardiac remodeling after myocardial infarction (MI) remains limited. Here we show that the level of circCEBPZOS is downregulated in serum EVs of patients with the adverse cardiac remodeling compared with those without post-MI remodeling or normal subjects. Loss-of-function approaches in vitro establish that circCEBPZOS robustly promote angiogenesis. Overexpression of circCEBPZOS in mice attenuates MI-induced left ventricular dysfunction, accompanied by a larger functional capillary network at the border zone. Further exploration of the downstream target gene indicates that circCEBPZOS acts as a competing endogenous RNA by directly binding to miR-1178-3p and thereby inducing transcription of its target gene phosphoinositide-dependent kinase-1 (PDPK1). Together, our results reveal that circCEBPZOS attenuates detrimental post-MI remodeling via the miR-1178-3p/PDPK1 axis, which facilitates revascularization, ultimately improving the cardiac function. The circular RNA circCEBPZOS, present in extracellular vesicles, promotes revascularization and alleviates postinfarct cardiac remodeling.

Automated summary

Emerging studies reveal the important roles of extracellular vesicles (EVs) and their inner circular RNAs (circRNAs) in gene regulation and cardiovascular repair. However, the understanding of EV-derived circRNAs in cardiac remodeling after myocardial infarction (MI) is limited. Here, it is demonstrated that circCEBPZOS is downregulated in serum EVs of patients with adverse cardiac remodeling after MI. In vitro experiments show that circCEBPZOS promotes angiogenesis. In vivo overexpression of circCEBPZOS in mice attenuates MI-induced left ventricular dysfunction and enhances revascularization.