Abstract
Activation of peroxisome proliferator-activated receptor gamma (PPARγ) in the cerebrovascular endothelium is a key suppressor of post-stroke brain damage. However, the role of PPARγ’s co-regulators during cerebral ischemia remains largely unknown. Here, we show that the transcription factor IRF6 is a novel PPARγ co-regulator that directly binds to and suppresses PPARγ activity in murine cerebrovascular endothelial cells. Moreover, IRF6 was also revealed to be a transcriptional target of PPARγ suppression, with PPARγ 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 PPARγ’s transcriptional inhibition of the ischemia-induced, pro-apoptotic microRNA miR-106a. In conclusion, we identified IRF6 as a novel PPARγ co-suppressor that serves a key role in suppressing PPARγ-mediated cerebrovascular endothelial cytoprotection following ischemia. Further investigation into IRF6 and other PPARγ co-regulators should provide additional insights into PPARγ’s cytoprotective role in the cerebrovascular endothelium following stroke.
Highlights
In the current study, we characterize interferon regulatory factor 6 (IRF6)’s role as a novel PPARγ co-repressor in the ischemic cerebrovascular endothelial cells
We found that IRF6 significantly inhibits PPAR binding sites (PPREs) activity under conditions of adenovirus-driven PPARγ overexpression, but IRF6 did not significantly affect PPRE activity at basal PPARγ expression levels (p < 0.05, Fig. 1C)
Pioglitazone-driven PPARγ activation significantly inhibited IRF6 mRNA expression (p < 0.05, Fig. 1D,E). These findings demonstrate that IRF6 is a PPARγ co-regulator that inhibits PPARγ activity in cerebrovascular endothelial cells
Summary
We characterize IRF6’s role as a novel PPARγ co-repressor in the ischemic cerebrovascular endothelial cells. Caspase-3 activity levels in isolated cerebral microvessels as well as murine cerebrovascular endothelial cells were assayed as previously described by Yin et al with minor modifications[17]. MiR-106a expression in the murine cerebrovascular endothelial cells or the isolated cerebral vessels was assayed as previously described by Yin et al with minor modifications[17].
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