LncRNA HOTAIRM1 Involved in Nano NiO-Induced Pulmonary Fibrosis via Regulating PRKCB DNA Methylation-Mediated JNK/c-Jun Pathway

Abstract

Abstract Nickel oxide nanoparticles (Nano NiO) lead to pulmonary fibrosis, and the mechanisms are associated with epigenetics. This study aimed to clarify the regulatory relationship among long noncoding RNA HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1), DNA methylation and expression of protein kinase C beta (PRKCB), and JNK/c-Jun pathway in Nano NiO-induced pulmonary fibrosis. Therefore, we constructed the rat pulmonary fibrosis model by intratracheal instillation of Nano NiO twice a week for 9 weeks and established the collagen deposition model by treating BEAS-2B cells with Nano NiO for 24 h. Here, the DNA methylation pattern was analyzed by whole-genome bisulfite sequencing in rat fibrotic lung tissues. Then, we integrated mRNA transcriptome data and found 93 DNA methylation genes with transcriptional significance. Meanwhile, the data showed that Nano NiO caused the down-regulation of lncRNA HOTAIRM1, the hypomethylation, and up-regulation of PRKCB2, JNK/c-Jun pathway activation, and collagen deposition (the up-regulated Col-I and α-SMA) both in vivo and in vitro. DNMTs inhibitor 5-AZDC attenuated Nano NiO-induced PRKCB2 expression, JNK/c-Jun pathway activation, and collagen deposition, but overexpression of PRKCB2 aggravated the changes mentioned indicators in Nano NiO-induced BEAS-2B cells. Furthermore, JNK/c-Jun pathway inhibitor (SP600125) alleviated Nano NiO-induced excessive collagen formation. Additionally, overexpression of HOTAIRM1 restrained the PRKCB hypomethylation, the activation of JNK/c-Jun pathway, and collagen formation induced by Nano NiO in BEAS-2B cells. In conclusion, these findings demonstrated that HOTAIRM1 could arrest Nano NiO-induced pulmonary fibrosis by suppressing the PRKCB DNA methylation-mediated JNK/c-Jun pathway.