Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy

Faisal Adhami, Guanghong Liao, Yury M. Morozov, Aryn Schloemer, Vincent J. Schmithorst, John N. Lorenz, R. Scott Dunn, Charles V. Vorhees, Marsha Wills-Karp, Jay L. Degen, Roger J. Davis, Noboru Mizushima, Pasko Rakic, Bernard J. Dardzinski, Scott K. Holland, Frank R Sharp, Chia Yi Kuan

Research output: Contribution to journalArticle

271 Scopus citations

Abstract

Hypoxia is a critical factor for cell death or survival in ischemic stroke, but the pathological consequences of combined ischemia-lrypoxia 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 fetures 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.

Original languageEnglish (US)
Pages (from-to)566-583
Number of pages18
JournalAmerican Journal of Pathology
Volume169
Issue number2
DOIs
StatePublished - Aug 2006

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Adhami, F., Liao, G., Morozov, Y. M., Schloemer, A., Schmithorst, V. J., Lorenz, J. N., Dunn, R. S., Vorhees, C. V., Wills-Karp, M., Degen, J. L., Davis, R. J., Mizushima, N., Rakic, P., Dardzinski, B. J., Holland, S. K., Sharp, F. R., & Kuan, C. Y. (2006). Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. American Journal of Pathology, 169(2), 566-583. https://doi.org/10.2353/ajpath.2006.051066