STAT-Dependent Upregulation of 12/15-Lipoxygenase Contributes to Neuronal Injury after Stroke

Abstract

Oxidative stress is a major brain injury mechanism after ischemic stroke. 12/15-lipoxygenase (12/15-LOX) is a key mediator of oxidative stress, contributing to neuronal cell death and vascular leakage. Nonetheless, the mechanism leading to its upregulation is currently unknown. We show here that Signal Transducers and Activators of Transcription (STATs), specifically STAT6 and possibly STAT1, increase transcription of 12/15-LOX in neuronal cells. Both p-STAT6 and -1 bound to specific STAT binding sites in the mouse 12/15-LOX promoter. Small interfering RNA (siRNA) knockdown showed STAT6 to be the dominant regulator, reducing 12/15-LOX promoter activation and cell death in oxidatively stressed HT22 cells. STAT6 siRNA efficiently prevented the increase of 12/15-LOX in murine primary neurons, both after induction of oxidative stress and after oxygen-glucose deprivation. Early activation of STAT6 and STAT1 in mice was consistent with a role in regulating 12/15-LOX in focal ischemia. Brains of human stroke patients showed increased p-STAT6 and p-STAT1 in the peri-infarct region, along with 12/15-LOX and markers of apoptosis. These results link STAT6 and STAT1 to the 12/15-LOX damage pathway and suggest disregulation of STAT-dependent transcription as injury mechanism in stroke. Selectively targeting STATs may thus be a novel therapeutic approach to reducing brain injury after a stroke.

STAT6/Arg1 promotes microglia/macrophage efferocytosis and inflammation resolution in stroke mice

“…The pSTAT6 staining partially overlapped with DAPI nuclei staining (Supplemental Figure 2, C-E). The pSTAT6 signal was also noted in some Iba1cells in both nonstroke and stroke brains, consistent with a previous report suggesting STAT6 activation in other types of cells in diseased or aging human brains (14).…”

“…Interestingly, pSTAT6 signal was detected in Iba1cells in both stroke patients and nonstroke aged brain. This is consistent with a previous report by Jung et al that documented STAT6 expression in the peri-infarct region of brains from stroke patients (14). Jung et al's study -while it did not use cellular markers to specify cell type in human samples -reported STAT6 activation in oxidatively stressed neurons in culture, with elevated STAT6 activity leading to neuronal death.…”

“…STAT6 deficiency impairs the clearance of dead/dying neurons, exacerbates local inflammation, enlarges brain tissue loss, and worsens long-term functional deficits. The activation of STAT6 in the ischemic brain has been previously reported in experimental animals at 3-12 hours after tMCAO and in brain slices from stroke patients (14,19). However, the specific cell type in which this activation occurs has not been previously identified.…”

Pathogenesis of Ischemic Stroke: Role of Epigenetic Mechanisms

“…The LcnRNA MEG3 was shown to be overexpressed in the brain of the MCAO mice, along with the upregulation of p53 and of 12/15-Lipoxygenase (12/15-LOX), two activators of cell death [103,104]. Specifically, MEG3 was found to interact with p53 during ischemia, allowing the activation of neuronal cell apoptosis.…”

Cancer Stem Cells: «Emergency Service» for Tumors Under Generalized Cellular Stress

“…Однако существуют и достаточно убедительные прямые доказательства индукции стволовости в ответ на оксидативный стресс [77][78][79]. Мы нашли доказательства активирующего действия оксидативного стресса для 34 генов из нашего списка: Abca1 [80], Acpp [81], Aldh1a1 [82], Alox15 [83], Arg2 [84], Blnk [46], Ccr3 [85], Cd200 [86], Cd55 [87], Col3a1 [88], Comp [89], Cp [90], Eef1a2 [91], Fgfr1 [92], Gas6 [93], Gstm3 [94], Igf1 [95], Igf2 [96], Il10 [97], Lyve1 [95], Mmp2 [98], Nfatc2 [99], Pde4d [100], Pdk4 [101], Per2 [102], Pon1 [103], Prg4 [104], Rragd [105], Selp [106], Serpinb1a [107], Serpinb2 [108,109], Slc2a4 [110], Tal1 [111], Wnt5a [112].…”