The Transcription Factor IRF6 Co-Represses PPARγ-Mediated Cytoprotection in Ischemic Cerebrovascular Endothelial Cells

Activation of peroxisome proliferator-activated receptor gamma ( PPAR.) in the cerebrovascular endothelium is a key suppressor of post-stroke brain damage. However, the role of PPAR gamma's co-regulators during cerebral ischemia remains largely unknown. Here, we show that the transcription factor IRF6 is a novel PPAR gamma co-regulator that directly binds to and suppresses PPAR. activity in murine cerebrovascular endothelial cells. Moreover, IRF6 was also revealed to be a transcriptional target of PPAR gamma suppression, with PPAR. silencing significantly promoting IRF6 expression in cerebrovascular endothelial cells. In addition, IRF6 silencing significantly promoted pioglitazone's cytoprotective effects in ischemic murine cerebrovascular endothelial cells. Mechanistically, IRF6 significantly suppressed PPAR gamma's transcriptional inhibition of the ischemia-induced, pro-apoptotic microRNA miR-106a. In conclusion, we identified IRF6 as a novel PPAR gamma co-suppressor that serves a key role in suppressing PPAR gamma-mediated cerebrovascular endothelial cytoprotection following ischemia. Further investigation into IRF6 and other PPAR gamma co-regulators should provide additional insights into PPAR gamma's cytoprotective role in the cerebrovascular endothelium following stroke.