Macrophage-specific circular RNA circHIPK2, inflammation, and fibrosis after myocardial infarction

Background and Aims: Cardiac remodelling following MI is intricately linked to macrophage polarization dynamics, yet the underlying mechanisms remain incompletely elucidated. In this study, circHIPK2, a novel circRNA, was identified as being upregulated in inflammatory cardiac macrophages following MI. Its expression correlated with post-MI inflammation dynamics, suggesting a regulatory role in macrophage polarization. It was hypothesized that circHIPK2 functions as a molecular switch of macrophage polarization during MI progression. Methods: To test this hypothesis, circHIPK2 levels were modulated in vitro using siRNA and overexpression vectors. A murine MI model with macrophage-targeted inhibition of circHIPK2 through AAV9-mediated shRNA delivery was employed. Cardiac function was evaluated using echocardiography, histology, and PET imaging. An ex vivo co-culture platform incorporating living myocardial slices from heart failure patients and circHIPK2-modulated human iPSC-derived macrophages was established to explore a translational potential. Results: CircHIPK2 interacts with its binding partner G3BP1 to promote stress granule formation in macrophages. This interaction initiates a downstream inflammatory cascade, highlighting its role in immune regulation. Inhibition of circHIPK2 suppressed inflammatory signalling and reduced pro-inflammatory cytokine secretion. In a mouse model of MI, macrophage-specific inhibition of circHIPK2 improved cardiac function, reshaped the inflammatory environment, and attenuated fibrosis progression. Silencing circHIPK2 in human macrophages demonstrated therapeutic potential in established heart failure, promoting beneficial cardiac healing. Conclusions: Targeting circHIPK2 in macrophages may represent a promising therapeutic strategy for treating inflammatory cardiac conditions and heart failure, potentially leading to the development of RNA-based therapies targeting immune cells in MI treatment.