Asiaticoside might attenuate bleomycin‐induced pulmonary fibrosis by activating cAMP and Rap1 signalling pathway assisted by A2AR

Abstract

Asiaticoside (AS) has been reported to have protective effect on pulmonary fibrosis (PF). In this study, we aimed to explore the potential mechanism of the therapeutic role of AS and its relationship with A2AR in PF. Adenosine 2A receptor gene knockout (A2AR −/− ) mice and wild‐type (WT) mice were used to establish bleomycin (BLM)‐induced PF models and were then treated with AS (50 mg/kg/d). Pulmonary inflammation and fibrosis were observed in the PF model with much higher severity in A2AR −/− mice than that in WT mice and AS significantly alleviated lung inflammation and fibrosis; however, it was less effective in A2AR −/− mice than in WT mice via histopathological analysis. Using RNA sequencing analysis, we found up‐regulated differentially expressed genes (DEGs) in BLM group were enriched in immune and inflammation‐associated pathways compared with control group. There were 242 common DEGs between down‐regulated in BLM vs control group and up‐regulated in BLM + AS vs BLM group, which were enriched in cAMP and Rap1 signalling pathways. Furthermore, the expression of five key factors of these two pathways including adenylate cyclase ( ADCY1 , ADCY5 , ADCY8 , cAMP and Rap1) were confirmed up‐regulated by AS with the presence of A2AR. Therefore, AS might attenuate BLM‐induced PF by activating cAMP and Rap1 signalling pathways which is assisted by A2AR, making it a promising therapeutic optional for PF.

Asiaticoside alleviates cardiomyocyte apoptosis and oxidative stress in myocardial ischemia/reperfusion injury via activating the PI3K-AKT-GSK3β pathway in vivo and in vitro

“…AS could induce type-I collagen synthesis to promote the repair of skin (8). Extensive pharmacological research have demonstrated that AS exerts anti-inflammatory (9), anti-tumor (10), antioxidant (11), and anti-fibrosis (12) effects, among others. The latest research showed the protective effect of AS against cerebral I/R injury via downregulating the NOD2/ MAPK/NF-κB pathway in rats (13).…”

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“…As a key pathway, Rap1 signaling pathway is related to respiratory system, cardiovascular system, and nervous system sequelae. Some experiments have confirmed that drugs can activate the Rap1 signaling pathway to restrict blood vessel formation and improve the symptoms of pulmonary fibrosis by regulating genes related to the Rap1 signaling pathway [ 156 , 157 ]. The Rap1 signaling pathway can regulate the differentiation of bone marrow mesenchymal stem cells and play a role in the treatment of cardiovascular diseases [ 158 ].…”

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“…Sphingolipid signaling has been shown to regulate a variety of cellular processes and has been implicated in collagen gene regulation 28 .Previous studies improved the glycerophospholipid metabolism can ameliorate liver brosis 29 . The Epac1/Rap1 pathway contributed to the main effect of cAMP on renal brosis 30,31 . Correlation analysis between transcriptomics and proteomics showed signi cant pathway was longevity regulating pathway-worm and FoxO signaling pathway.…”