Regulation of VEGF Expression in Hypoxic Pulmonary Artery Endothelial Cells (PAECs) by Base Excision DNA Repair (BER) Activity

Abstract

Reactive species generated by peri‐nuclear mitochondria cause formation of the common base oxidation product 8‐oxoguanine (8‐ oxoG) in hypoxic response elements (HRE) of inducible genes (Al‐Mehdi et al., Sci Signaling, 2012). Repair 8‐oxoG by the BER pathway is initiated by the lesion‐specific DNA glycosylase OGG1. The specific mechanism whereby DNA repair interacts with transcription is still unknown. We tested the idea that modulation of OGG1 alters transcription complex formation on the VEGF HRE and VEGF mRNA expression. In cultured PAECs, we confirmed that hypoxia increased 8‐oxoG in the VEGF HRE. siRNA‐mediated knockdown and transgenic over‐expression of OGG1 increased and decreased, respectively, the proportion of VEGF HREs harboring 8‐oxoG. The hypoxia‐induced increase in HRE sequences associating with Hif‐1 was inhibited by OGG1 knockdown and augmented by OGG1 over‐expression. Hypoxia‐induced Vegf mRNA expression tracked Hif‐1 binding in cells with modulated OGG1 activity. These findings indicate that the BER pathway may be important for transcription and point to new mechanisms linking hypoxia to mutagenesis, aging and other oxidant‐related disorders.Supported by NIH.