Inhibition of VCAM-1 gene transcriptional blockade by RHOdiroside through inhibition of P65 and CSN5 deubiquitination reduces atherosclerosis in monocytes and endothelial adherent cells

Abstract

Abstract Monocyte-endothelial cell adhesion plays a crucial role in the early development of atherosclerosis, contributing to lipid disruption and exacerbating the condition. RHOdiola (RHO), a prominent Chinese medicinal drug, possesses diverse pharmacological activities such as anti-inflammatory, antioxidant, anti-cancer, anti-metabolic deregulation, and neuroprotective effects. However, the specific anti-atherosclerotic effects of RHO remain incompletely understood. Thus, this study aimed to investigate the potential beneficial impact of RHO on atherosclerosis. ApoE-/- mice were fed a high-fat diet and administered RHO treatment. Protein expression levels of GATA2, CSN5, and VCAM-1 in the aortic endotheliμM were evaluated. Our findings demonstrate a reduction in GATA2, CSN5, and VCAM-1 protein expression levels in the aortic endotheliμM, accompanied by decreased P65 phosphorylation levels. Additionally, GATA2 ubiquitination was downregulated, The binding strength of PP2AC and I2PP2A decreased while its binding to P65 increased. Moreover, RHO directly inhibited the transcriptional activity of NF-κB subunit P65 as a transcription factor by targeting the I2PP2A-PP2Ac axis. Furthermore, it interacted with the transcription factor GATA-2 through CSN5-mediated deubiquitination, thereby directly suppressing the transcription of the P65-regulated VCAM-1 gene. In conclusion, the combined dual inhibition of VCAM-1 gene transcription, along with the consequent reduction in monocyte-endothelial cell adhesion, mediates the anti-atherosclerotic biological activity exerted by RHO.