The high-mobility group I-Y transcription factor is involved in cerebral ischemia and modulates the expression of angiogenic proteins

Abstract

The present study aims to identify transcription factors (TFs) contributing to angiogenesis, a mechanism involved in giving plasticity to the brain, as potential therapeutic targets after cerebral ischemia. The promoter sequences from candidate genes involved in angiogenesis were submitted to a comparative analysis by bioinformatics software. High-mobility group I-Y protein (HMGIY) TF characterization in a rat permanent focal cerebral ischemia model was performed by quantitative real time polymerase chain reaction and Western blot for the TF expression profile study. The TF functional study was carried out using a TF-TF interaction array and gene silencing by siRNA in rat brain microvascular endothelial cells. The results showed that the promoters shared a common TF binding site for HMGIY. The expression profile analysis in ischemic rat brain showed an increase in HMGIY mRNA in the acute phase and a progressive overexpression of protein over time post-ischemia. The interaction array analysis revealed that ischemia promotes the interaction of HMGIY with TFs involved in different cerebral plasticity processes. In vitro knockdown studies showed that angiopoietin 1 and vascular endothelial growth factor expression is controlled by HMGIY and that this TF is involved in cell survival in brain endothelial cells. These findings suggest that HMGIY is a potential therapeutic target that could promote brain repair functions after stroke.

Keywords: HMGIY; angiogenesis; brain microvascular endothelial cells; brain plasticity; cerebral ischemia; transcription factor.