MicroRNA-98 inhibition accelerates the development of atherosclerosis via regulation of dysfunction of endothelial cell

Background Atherosclerosis has been recognized as a chronic inflammation initiated by dysfunction of endothelial cell that contributes to the increased morbidity and mortality of severe cardiovascular events. The reported important role of microRNA-98 (miR-98) in regulation of endothelial cell behaviors prompt us to hypothesize that miR-98 could be involved in the process of atherosclerosis. Methods and Results The current research showed the miR-98 expression was gradually down-regulated in atherosclerotic mouse arteries isolated from ApoE ablation mice subjected to high fat diet. Additionally, a dramatically reduced miR-98 expression in endothelial cells administrated to oxidized low-density lipoprotein (Ox-LDL) but a slight down-regulated level was found in macrophages. Functionally, attenuated miR-98 expression promoted secretion of chemokines and adhesion molecules in human umbilical vein endothelial cells (HUVECs) induced by Ox-LDL, which subsequently increased infiltration and pro-inflammatory genes expression of macrophages, as well as the foam cell formation. Mechanistically, in vitro experiments indicated that the endothelial cell dysfunction regulated by miR-98 knockdown was partially contributed by upregulated expression of HMGB1. Furthermore, the animal experiment with ApoE(-/-) mice administrated with miR-98 inhibitor demonstrated that miR-98 silencing enhanced the atherosclerotic lesions in aorta and aortic sinus that were accompanied with increased adhesion molecules, chemokines, and pro-inflammatory markers expression. Conclusion MicroRNA-98 knockdown promoted endothelial cell dysfunction to affect the inflammatory state of macrophage and the development of atherosclerosis, at least partially, through direct targeting HMGB1. Collected, these data suggested that miR-98 could be a novel drug target for atherogenesis management.

Automated summary

This study found that the expression of miR-98 gradually decreased in atherosclerotic mouse arteries under high-fat diet conditions. Furthermore, the expression of miR-98 was significantly reduced in endothelial cells treated with oxidized low-density lipoprotein (ox-LDL), while it was slightly decreased in macrophages. Functionally, the downregulation of miR-98 promoted the secretion of chemokines and adhesion molecules in human umbilical vein endothelial cells (HUVECs) induced by ox-LDL, leading to increased infiltration of macrophages and expression of pro-inflammatory genes, as well as foam cell formation. The findings suggest that miR-98 could be a novel drug target for the management of atherosclerosis.