The serine protease Omi/HtrA2 is involved in XIAP cleavage and in neuronal cell death following focal cerebral ischemia/reperfusion.
Omi/HtrA2 is a pro-apoptotic mitochondrial serine protease involved in both forms of apoptosis, caspase-dependent as well as caspase-independent cell death. However, the impact of Omi/HtrA2 in the apoptotic cell machinery that takes place in vivo under pathological conditions such as cerebral ischemia remains unknown. The present study was monitored in order to examine whether Omi/HtrA2 plays a decisive role in apoptosis observed after focal cerebral ischemia in rats. Male adult rats were subjected to 90min of focal cerebral ischemia followed by reperfusion and treated with vehicle or ucf-101, a novel and specific Omi/HtrA2 inhibitor, prior reperfusion. Focal cerebral ischemia/reperfusion induced a mitochondrial up-regulation of Omi/HtrA2 and significantly increased cytosolic accumulation of Omi/HtrA2. Furthermore, ischemia led to activation of caspase-3 and degradation X-linked inhibitor of apoptosis protein (XIAP). Treatment of animals prior ischemia with ucf-101, the specific inhibitor of Omi/HtrA2, was able to (1) reduce the number of TUNEL-positive cells, to (2) attenuate the XIAP-breakdown and to (3) reduce the infarct size. This study shows for the first time that focal cerebral ischemia in rats results in Omi/HtrA2 translocation from the mitochondria to the cytosol, where it participates in neuronal cell death. Blocking the proteolytic activity of Omi/HtrA2 with specific inhibitors, such as the ucf-101, could be a novel way to afford neuroprotection and minimize cellular damage in cerebral ischemia/reperfusion.
Althaus
J
J
Institut für Zelluläre und Molekulare Anatomie (Anatomie III), Johann Wolfgang von Goethe-Universität, Theodor-Stern-Kai 7, 60590 Franfurt, Main, Germany.
Siegelin
M D
MD
Dehghani
F
F
Cilenti
L
L
Zervos
A S
AS
Rami
A
A
D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology; D005260:Female; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006868:Hydrolysis; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009474:Neurons; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology; D012697:Serine Endopeptidases / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
D024101:Mitochondrial Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2