Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy.
Hypoxia is a critical factor for cell death or survival in ischemic stroke, but the pathological consequences of combined ischemia-hypoxia are not fully understood. Here we examine this issue using a modified Levine/Vannucci procedure in adult mice that consists of unilateral common carotid artery occlusion and hypoxia with tightly regulated body temperature. At the cellular level, ischemia-hypoxia produced proinflammatory cytokines and simultaneously activated both prosurvival (eg, synthesis of heat shock 70 protein, phosphorylation of ERK and AKT) and proapoptosis signaling pathways (eg, release of cytochrome c and AIF from mitochondria, cleavage of caspase-9 and -8). However, caspase-3 was not activated, and very few cells completed the apoptosis process. Instead, many damaged neurons showed features of autophagic/lysosomal cell death. At the tissue level, ischemia-hypoxia caused persistent cerebral perfusion deficits even after release of the carotid artery occlusion. These changes were associated with both platelet deposition and fibrin accumulation within the cerebral circulation and would be expected to contribute to infarction. Complementary studies in fibrinogen-deficient mice revealed that the absence of fibrin and/or secondary fibrin-mediated inflammatory processes significantly attenuated brain damage. Together, these results suggest that ischemia-hypoxia is a powerful stimulus for spontaneous coagulation leading to reperfusion deficits and autophagic/lysosomal cell death in brain.
Adhami
Faisal
F
Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Room 3464, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
Liao
Guanghong
G
Morozov
Yury M
YM
Schloemer
Aryn
A
Schmithorst
Vincent J
VJ
Lorenz
John N
JN
Dunn
R Scott
RS
Vorhees
Charles V
CV
Wills-Karp
Marsha
M
Degen
Jay L
JL
Davis
Roger J
RJ
Mizushima
Noboru
N
Rakic
Pasko
P
Dardzinski
Bernard J
BJ
Holland
Scott K
SK
Sharp
Frank R
FR
Kuan
Chia-Yi
CY
D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D001921:Brain / Q000098:blood supply / Q000166:cytology / Q000473:pathology / Q000648:ultrastructure; D001929:Brain Edema / Q000473:pathology; D020520:Brain Infarction / Q000473:pathology; D002470:Cell Survival; D016207:Cytokines / Q000096:biosynthesis; D004211:Disseminated Intravascular Coagulation / Q000503:physiopathology*; D005337:Fibrin / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000139:chemically induced*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012039:Regional Blood Flow; D015424:Reperfusion; D015398:Signal Transduction
D016207:Cytokines; D005337:Fibrin