Activation of Lysine Demethylases (KDM's) by Intermittent Hypoxia

Abstract

We previously reported that intermittent hypoxia (IH), a hallmark of sleep apnea, increases reactive oxygen species (ROS) in the central and peripheral nervous system. IH‐induced increase in ROS abundance was in part due to hypoxia‐inducible factor (HIF)‐1 dependent transcriptional up regulation of NADPH oxidase (Nox)‐2 and 4. Emerging evidence suggests that lysine demethylases (KDM's) acting as co‐activators contribute to HIF‐1‐dependent transcriptional activation. The aim of the present study is to assess whether KDM proteins contribute to IH‐evoked Nox4 transcriptional activation by HIF‐1. Experiments were performed on rat pheochromocytoma (PC12) cells treated with alternating cycles of 1.5% O2 for 30 sec followed by 20% O2 for 5 min. Protein abundance and activities of KDM2A, KDM4A, 4B, 4C and KDM6B in nuclear extracts were analyzed by immunoblot and colorimetric assays, respectively. Cells treated with 60 cycles of IH (IH60) showed increased protein abundance and activity of KDM6B. Co‐immunoprecipitation assays showed that KDM6B interacts with HIF‐1α and blockade of KDM6B with silencing RNA prevented Nox4 transcriptional activation by HIF‐1. These findings demonstrate that KDM6B functions as a coactivator of HIF‐1 mediated transactivation of Nox4 by IH.Support or Funding InformationSupported by NIH‐HL‐90554.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.