Silencing ARL11 relieved atherosclerotic inflammation and lipid deposition via retraining JAK2/STAT1 pathway.

Abstract

BACKGROUND AND AIMS: Atherosclerosis (AS), an arterial vasculature disease, is characterized by abnormal lipid accumulation and inflammatory response. ADP ribosylation factor like GTPase 11 (ARL11) is linked to multifarious processes in cells. This study aims to clarify the underlying mechanism of ARL11 in AS. METHODS: ApoEmice fed with high-fat diet were used as mouse model of AS. Gene expression in AS was determined by mRNA-sequencing. ARL11 expression was detected by real-time PCR, Western blot and immunofluorescence. M1 polarization of macrophages was indicated by TNF-α and IL-6 levels as detected with ELISA, and iNOS expression determined by real-time PCR and Western blot. The role of ARL11 during AS was explored through loss-of-function analysis. RESULTS: There were 1301 upregulated and 1110 downregulated genes during AS. These differentially expressed genes (DEGs) were mainly enriched in pathways and terms which are involved in inflammation. Moreover, Arl11 was highly expressed in AS models. Downregulation of Arl11 decreased lipid deposition and atherosclerotic plaques in the aortas of AS mice, and declined inflammatory cytokines and M1 polarization of macrophages induced by IFN-γ. Furthermore, ARL11 interacted with JAK2 and p-JAK2 and modulated their degradation, thus inhibiting the activation of JAK2/STAT1 pathway. CONCLUSIONS: ARL11 promoted the development of AS via interacting with JAK2 and activating JAK2/STAT1 pathway. Thus, silencing ARL11 may prevent the process of AS and be a novel way to treat AS.