Abstract
The major cause of cardiovascular disease is atherosclerosis, which develops preferentially at arterial branches and curvatures. The fluid shear stress (FSS) in these regions is oscillatory shear stress (OSS). OSS has been shown to play important roles in modulating various responses involved in endothelial cell (EC) dysfunction. The other kind of fluid shear stress is pulsatile shear stress (PSS), which generally occurs in areas spared from atherosclerotic lesions. Therefore, FSS is considered as an important factor to modulate inflammation and atherosclerosis in vascular wall. Recently, miRNA-10a has been identified as an anti-inflammatory molecule in athero-susceptible regions in vivo. However, whether miRNA-10a can be regulated by different FSS patterns and the detailed mechanisms involved in this mechanotransduction remain unclear. In the present study, we investigated the role of miRNA-10a in regulating inflammatory responses of ECs to different FSS patterns. Application of OSS (0.5 ± 4 dynes/cm2) and PSS (12 ± 4 dynes/cm2) to HUVECs can sustainably down-regulate and up-regulate miRNA-10a expression, respectively. This flow-regulated miRNA-10a expression could consequently regulate the expression of its directed target GATA-6 and downstream vascular cell adhesion molecule-1 (VCAM-1). Transfecting ECs with RARα-specific siRNA could totally inhibit PSS-induced miRNA-10a expression, but RXRα-specific siRNA could only partially inhibit this response. The vascular of ApoE-/- mice fed with high-cholesterol diet express atherosclerotic lesions formation. Administration of PreR-10a can enhance miRNA-10a expression in the vascular endothelial cell and prevent atherosclerotic lesions formation. These results suggest that RARα/RXRα could constitute regulatory complex to switch miRNA-10a expression in response to different FSS patterns in regulating inflammatory response and atherosclerosis formation.