MiR-328-5p functions as a critical negative regulator in early endothelial inflammation and advanced atherosclerosis

Abstract

Abstract Early proatherogenic inflammation is a major risk factor for the development of atherogenesis. However, the molecular mechanisms underlying this pathological process remain largely unknown. In this study, we have discovered that the microRNA miR-328-5p negatively regulates endothelial inflammation by controlling the stability of JUNB. Disruption of miR-328-5p markedly augments monocyte adhesion to endothelial cells and their transendothelial migration. Consistently, enforced overexpression of miR-328-5p mimics shows a strong resistance to endothelial inflammation characterized by reduced monocyte adhesion with endothelial cells, monocyte transendothelial migration to the endothelium and production of key pro-inflammatory factors. Moreover, miR-328-5p significantly dampens the conversion of macrophages to M1-type polarization. An in vivo study illustrates that miR-328-5p negatively modulates atherosclerotic plaque formation. Interestingly, JUNB, a crucial regulator to trigger inflammatory response, is found to be a direct target for miR-328-5p. Reintroduction of JUNB was able to rescue the significant inhibition of atherosclerosis caused by miR-328-5p. Overall, these findings suggest an inhibitory role of miR-328-5p in proatherogenic process, at least in part, by controlling the abundance of JUNB. Thus, pharmacological targeting of miR-328-5p might be a beneficial strategy for the clinical treatment of inflammatory atherosclerosis.