CircNPHP4 in monocyte-derived small extracellular vesicles controls heterogeneous adhesion in coronary heart atherosclerotic disease

Abstract

Small extracellular vesicles (sEVs)-derived circular RNAs (circRNAs) could regulate gene expression in recipient cells, and dysregulation of sEVs-derived circRNAs has been implicated in several diseases. However, the expression and function of sEVs-derived circRNAs in coronary heart atherosclerotic disease (CAD) remain unknown. In this study, we investigated global changes in the expression patterns of circRNAs in sEVs from CAD-related monocytes and identified circNPHP4 as a significantly upregulated circRNA. Knockdown of circNPHP4 inhibited heterogeneous adhesion between monocytes and coronary artery endothelial cells and reduced ICAM-1 and VCAM-1 expression. Investigations of the underlying mechanisms revealed that circNPHP4 contains a functional miR-1231-binding site. Mutation of the circNPHP4-binding sites in miR-1231 abolished the interaction, as indicated by a luciferase reporter assay. Furthermore, circNPHP4 affected the expression of miR-1231 and its target gene EGFR. Overexpression of miR-1231 blocked the inhibitory effect of circNPHP4 on heterogeneous adhesion. Moreover, downregulation of miR-1231 restored heterogeneous adhesion upon inhibition by circNPHP4 silencing. Additionally, circNPHP4 overexpression was correlated with aggressive clinicopathological characteristics in CAD patients. A multivariate logistic regression model and bootstrapping validation showed that circNPHP4 overexpression had a good risk prediction capability for CAD. The decision curve analysis revealed that using the CAD nomogram that included circNPHP4 overexpression to predict the risk of CAD was beneficial. Our results suggest that sEVs-derived circNPHP4 can serve as a potential target for CAD treatments or as a potential diagnostic marker for CAD patients.

Extracellular vesicles and their non‐coding RNA cargos: Emerging players in cardiovascular disease

“…EXs containing miR‐106a from ox‐LDL‐exposed macrophages increased proliferation and repressed apoptosis in human SMCs (Liu, Zhang et al., 2020). Monocyte‐derived EVs containing circNPHP4 promoted heterogeneous adhesion between monocytes and coronary artery endothelial cells by sponging miR‐1231 and its target gene, epidermal growth factor receptor, in coronary atherosclerosis (Xiong et al., 2021). EXs containing lncRNA GAS5 from the human monocytic cell line THP‐1 play a role in atherogenesis by dysregulating macrophage and endothelial cell communication (Chen et al., 2017) (Fig.…”

The good, the bad and the ugly: the impact of extracellular vesicles on the cardiovascular system

“…Numerous miRNAs were found to be increased in the circulation of patients with CVDs, namely miR‐1 and miR‐133a, associated with the presence of myocardial damage (Kuwabara et al., 2011). More recently, the circular RNA (circRNA) circNPHP4 was found to be upregulated in monocyte‐derived EVs from CAD patients, being correlated with its clinicopathological status (Xiong et al., 2021).…”

Plasma Exosomal S1PR5 and CARNS1 as Potential Non-invasive Screening Biomarkers of Coronary Heart Disease

“…First, we extracted monocytes from plasma, and the result of analysis of monocytes can refer to Supplementary Figure S1 of our published article ( 10 ). Through transmission electron microscopy (TEM), we found that the sEVs were ~100 nm in diameter and conformed to the known shape of sEVs.…”