Published online before print November 11, 2002, doi: 10.1161/01.CIR.0000039103.58920.1F
(Circulation. 2002;106:2973.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Erythropoietin Is a Novel Vascular Protectant Through Activation of Akt1 and Mitochondrial Modulation of Cysteine Proteases
From the Division of Cellular and Molecular Cerebral Ischemia (Z.Z.C., J.-Q.K., K.M.), Departments of Neurology (Z.Z.C., J.-Q.K., K.M.) and Anatomy and Cell Biology (K.M.), Center for Molecular Medicine and Genetics (K.M.), Institute of Environmental Health Sciences (K.M.), Wayne State University School of Medicine, Detroit, Mich.
Correspondence to Kenneth Maiese, MD, Department of Neurology, 8C-1 UHC, Wayne State University School of Medicine, 4201 St Antoine, Detroit, MI 48201. E-mail kmaiese{at}med.wayne.edu
Background— Erythropoietin (EPO) is a critical regulator for the proliferation of immature erythroid precursors, but its role as a potential cytoprotectant in the cerebrovasculature system has not been defined.
Methods and Results— We examined the ability of EPO to regulate a cascade of apoptotic death-related cellular pathways during anoxia-induced vascular injury in endothelial cells (ECs). EC injury was evaluated by trypan blue, DNA fragmentation, membrane phosphatidylserine (PS) exposure, protein kinase B activity, mitochondrial membrane potential, and cysteine protease induction. Exposure to anoxia alone rapidly increased genomic DNA fragmentation from 2±1% to 40±5% and membrane PS exposure from 3±2% to 56±5% over 24 hours. Administration of a cytoprotective concentration of EPO (10 ng/mL) prevented DNA destruction and PS exposure. Cytoprotection by EPO was completely abolished by cotreatment with anti-EPO neutralizing antibody, which suggests that EPO was necessary and sufficient for the prevention of apoptosis. Protection by EPO was intimately dependent on the activation of protein kinase B (Akt1) and the maintenance of mitochondrial membrane potential. Subsequently, EPO inhibited caspase 8-, caspase 1-, and caspase 3-like activities that were linked to mitochondrial cytochrome c release.
Conclusions— The present work serves to illustrate that EPO can offer novel cytoprotection during ischemic vascular injury through direct modulation of Akt1 phosphorylation, mitochondrial membrane potential, and cysteine protease activity.
Key Words: apoptosis • cytochrome c • cysteine endopeptidases • proteins, mitochondrial • proteins, proto-oncogene
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