STAT-dependent upregulation of 12/15-lipoxygenase contributes to neuronal injury after stroke

Whom in the world is going to follow through with more research on this to see if we can stop some of the neuronal death post stroke? Because we have NO fucking leaders or strategy in stroke this promising research will never get followed up. You're screwed, your children are screwed, your grandchildren are screwed, all for a lack of leadership in stroke.
http://www.nature.com/jcbfm/journal/v35/n12/abs/jcbfm2015169a.html

Joo Eun Jung¹, Hulya Karatas^1,5, Yu Liu¹, Ayfer Yalcin^2,3, Joan Montaner⁴, Eng H Lo¹ and Klaus van Leyen¹

1. ¹Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
2. ²Department of Biochemistry, Faculty of Pharmacy, Ege University, Bornova, Izmir, Turkey
3. ³Biruni University, Faculty of Pharmacy, Istanbul, Turkey
4. ⁴Laboratorio de Investigación Neurovascular Hospital Vall d'Hebron, Barcelona, Spain

Correspondence: Dr K van Leyen, Neuroprotection Research Laboratory, Massachusetts General Hospital, 149 13th Street, Room 2401, Charlestown, Massachusetts 02129, USA. E-mail: klaus_vanleyen@hms.harvard.edu

⁵Current Address: Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara 06100, Turkey.

Received 10 December 2014; Revised 12 June 2015; Accepted 15 June 2015
Advance online publication 15 July 2015

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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.