CircHIPK3 regulates cardiac fibroblast proliferation, migration and phenotypic switching through the miR-152-3p/TGF-?2 axis under hypoxia.

ABSTRACT: Background:The occurrence of pathological cardiac fibrosis is attributed to tissue hypoxia. Circular RNAs play significant regulatory roles in multiple cardiovascular diseases and are involved in the regulation of physiological and pathophysiological processes. CircHIPK3 has been identified as the one of the most crucial regulators in cardiac fibrosis. However, the mechanisms by which circHIPK3 regulates cardiac fibrosis under hypoxia remain unclear. Our study aimed to determine circHIPK3 expression in cardiac fibroblasts (CFs) and investigate the functions of circHIPK3 in hypoxia environment. Methods:The expression level of circHIPK3 in CFs under hypoxia (1% O2) was analyzed by qRT-PCR. The role of circHIPK3 on the proliferation and migration of CFs were determined by EdU, cell wound scratch assay and cell cycle. The expression of proteins associated with phenotypic transformation in CFs in vitro was examined by immunofluorescence assay and western blot. Bioinformatics analysis, dual luciferase activity assay and RNA fluorescent in situ hybridization assay revealed that miR-152-3p was identified as a target of circHIPK3 and that TGF-?2 was targeted by miR-152-3p. Results:CircHIPK3 expression was significantly upregulated in CFs in a hypoxic environment. In vitro, overexpressing circHIPK3 obviously promoted CF proliferation, migration and phenotypic changes under hypoxia, but those processes were suppressed by circHIPK3 silencing. CircHIPK3 acted as an endogenous miR-152-3p sponge and miR-152-3p aggravated circHIPK3 silencing induced inhibition of CF proliferation, migration, phenotypic transformation and TGF-?2 expression in vitro. In summary, circHIPK3 plays a pivotal role in the development of cardiac fibrosis by targeting the miR-152-3p/TGF-?2 axis. Conclusions:These findings demonstrated that circHIPK3 acted as a miR-152-3p sponge to regulate CF proliferation, migration and phenotypic transformation through TGF-?2, revealing that modulation of circHIPK3 expression may represent a potential target to promote the transition of hypoxia-induced CFs to myofibroblasts.

SUBMITTER: Liu W 

PROVIDER: S-EPMC7453924 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature