Secreted tyrosine sulfated-eIF5A mediates oxidative stress-induced apoptosis.
Oxidative stress plays a critical role in ischemia/reperfusion-injury, atherosclerosis, and aging. It causes cell damage that leads to apoptosis via uncertain mechanisms. Because conditioned medium from cardiac myocytes subjected to hypoxia/reoxygenation induces extensive apoptosis of cardiac myocytes under normoxia, we hypothesized that a humoral factor released from the hypoxic/reoxygenated cardiac myocytes mediates apoptosis. We identified an apoptosis-inducing humoral factor in the hypoxia/reoxygenation-conditioned medium. Here, we found that eIF5A undergoes tyrosine sulfation in the trans-Golgi and is rapidly secreted from cardiac myocytes in response to hypoxia/reoxygenation; then, eIF5A induces apoptosis by acting as a pro-apoptotic ligand. The apoptosis of cardiac myocytes induced by hypoxia/reoxygenation or ultraviolet irradiation was suppressed by anti-eIF5A neutralizing monoclonal antibodies (mAbs) in vitro. Myocardial ischemia/reperfusion (but not ischemia alone) markedly increased the plasma levels of eIF5A, and treatment with anti-eIF5A neutralizing mAbs significantly reduced myocardial injury. These results identify an important, novel specific biomarker and a critical therapeutic target for oxidative stress-induced cell injury.
Department of Cardiovascular Medicine, The Institute for Adult Diseases, Asahi Life Foundation, 2-2-6 Nihonbashi-Bakurocho, Chuo-ku, Tokyo 103-0002, Japan.|Department of Immunology, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.
Yoshinori
Y
Seko
Division of Proteomics and Biomolecular Science, BioMedical Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.
Tsutomu
T
Fujimura
Department of Cardiovascular Medicine, The Institute for Adult Diseases, Asahi Life Foundation, 2-2-6 Nihonbashi-Bakurocho, Chuo-ku, Tokyo 103-0002, Japan.
Takako
T
Yao
Division of Proteomics and Biomolecular Science, BioMedical Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.
Hikari
H
Taka
Division of Proteomics and Biomolecular Science, BioMedical Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.
Reiko
R
Mineki
Department of Immunology, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.
Ko
K
Okumura
Division of Proteomics and Biomolecular Science, BioMedical Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.
Kimie
K
Murayama
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D004195:Disease Models, Animal; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D010100:Oxygen / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*; D021601:trans-Golgi Network / Q000378:metabolism; D000097574:Eukaryotic Translation Initiation Factor 5A
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D010100:Oxygen; D010446:Peptide Fragments; D010448:Peptide Initiation Factors; D016601:RNA-Binding Proteins; D014443:Tyrosine; D000097574:Eukaryotic Translation Initiation Factor 5A