RRC ID 1859
Author Adhami F, Liao G, Morozov YM, Schloemer A, Schmithorst VJ, Lorenz JN, Dunn RS, Vorhees CV, Wills-Karp M, Degen JL, Davis RJ, Mizushima N, Rakic P, Dardzinski BJ, Holland SK, Sharp FR, Kuan CY.
Title Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy.
Journal Am. J. Pathol.
Abstract 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.
Volume 169(2)
Pages 566-83
Published 2006-8
DOI 10.2353/ajpath.2006.051066
PII S0002-9440(10)62738-1
PMID 16877357
PMC PMC1780162
MeSH Animals Apoptosis Autophagy* Brain / blood supply Brain / cytology Brain / pathology Brain / ultrastructure Brain Edema / pathology Brain Infarction / pathology Cell Survival Cytokines / biosynthesis Disseminated Intravascular Coagulation / physiopathology* Fibrin / metabolism Hypoxia-Ischemia, Brain / chemically induced* Lysosomes / metabolism Male Mice Mice, Inbred C57BL Regional Blood Flow Reperfusion Signal Transduction
IF 3.762
Times Cited 208
Mice GFP-LC3#53