Role of Omi/HtrA2 in apoptotic cell death after myocardial ischemia and reperfusion.
BACKGROUND
Omi/HtrA2 is a proapoptotic mitochondrial serine protease involved in caspase-dependent as well as caspase-independent cell death. However, the role of Omi/HtrA2 in the apoptotic cell death that occurs in vivo under pathological conditions remains unknown. The present study was designed to investigate whether Omi/HtrA2 plays an important role in postischemic myocardial apoptosis.


RESULTS
Male adult mice were subjected to 30 minutes of myocardial ischemia followed by reperfusion and treated with vehicle or ucf-101, a novel and specific Omi/HtrA2 inhibitor, 10 minutes before reperfusion. Myocardial ischemia/reperfusion significantly increased cytosolic Omi/HtrA2 content and markedly increased apoptosis. Treatment with ucf-101 exerted significant cardioprotective effects, as evidenced by less terminal dUTP nick end-labeling staining, a lower incidence of DNA ladder fragmentation, and smaller infarct size. Furthermore, treatment with ucf-101 before reperfusion attenuated X-linked inhibitor of apoptosis protein degradation and inhibited caspase-9 and caspase-3 activities.


CONCLUSIONS
Taken together, these results demonstrate for the first time that ischemia/reperfusion results in Omi/HtrA2 translocation from the mitochondria to the cytosol, where it promotes cardiomyocyte apoptosis via a protease activity-dependent, caspase-mediated pathway.
Liu
Hui-Rong
HR
Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pa, USA.
Gao
Erhe
E
Hu
Aihua
A
Tao
Ling
L
Qu
Yan
Y
Most
Patrick
P
Koch
Walter J
WJ
Christopher
Theodore A
TA
Lopez
Bernard L
BL
Alnemri
Emad S
ES
Zervos
Antonis S
AS
Ma
Xin L
XL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D053148:Caspase 3; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D000074923:High-Temperature Requirement A Serine Peptidase 2; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology; D024101:Mitochondrial Proteins; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D011506:Proteins / Q000037:antagonists & inhibitors; D011744:Pyrimidinones / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000502:physiology*; D013871:Thiones / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein
D002316:Cardiotonic Agents; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D024101:Mitochondrial Proteins; D011506:Proteins; D011744:Pyrimidinones; D013871:Thiones; C501517:UCF 101; D051636:X-Linked Inhibitor of Apoptosis Protein; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases