Methylated Vnn1 at promoter regions induces asthma occurrence via the PI3K/Akt/NFκB-mediated inflammation in the IUGR mice

Abstract

Intrauterine growth retardation (IUGR) has high risk of developing bronchial asthma in childhood, whereas the underlying mechanisms remain unclear. This study aimed to disclose the role of vascular noninflammatory molecule 1 (vannin-1, encoded by the Vnn1 gene) and its downstream signaling in the IUGR asthmatic mice induced by ovalbumin. More significant histological alterations and increase of vannin-1 expressions were revealed in IUGR asthmatic mice, accompanied by elevated methylation of Vnn1 promoter regions. In IUGR asthmatic mice, we also found i) a direct binding of HNF4α and PGC1α to Vnn1 promoter by CHIP assay; ii) a direct interaction of HNF4α with PGC1α; iii) upregulation of phospho-PI3K p85/p55 and phospho-AktSer473 and downregulation of phospho-PTENTyr366; iv) increase in nuclear NFκB p65 and decrease in cytosolic IκB-α. In primary cultured bronchial epithelial cells derived from the IUGR asthmatic mice, knockdown of Vnn1 prevented upregulation of phospho-AktSer473 and increase of reactive oxygen species (ROS) and TGF-β production. Taken together, we demonstrate that elevated vannin-1 activates the PI3K/Akt/NFκB signaling pathway, leading to ROS and inflammation reactions responsible for asthma occurrence in IUGR. We also disclose that interaction of PGC1α and HNF4α promotes methylation of Vnn1 promoter regions and then upregulates vannin-1 expression.