Abstract
Oxidative stress is known to play a pivotal role in the pathogenesis of various disorders including atherosclerosis, aging and especially ischaemia/reperfusion injury. It causes cell damage that leads to apoptosis. However, the precise mechanism has been uncertain. Recently, we identified an apoptosis-inducing humoral factor in a hypoxia/reoxygenated medium of cardiac myocytes. We named this novel post-translationally modified secreted form of eukaryotic translation initiation factor 5A (eIF5A) as oxidative stress-responsive apoptosis inducing protein (ORAIP). We developed a sandwich ELISA and confirmed that myocardial ischaemia/reperfusion markedly increased plasma levels of ORAIP. To investigate whether the role of ORAIP is common to various typesof oxidative stress, we measured plasma ORAIP levels in rats subjected to three physicochemical models of oxidative stress including N2/O2 inhalation, cold/warm-stress (heat shock) and blood acidification. In all three models, plasma ORAIP levels significantly increased and reached a peak level at 10-30min after stimulation, then decreased within 60min. The (mean±S.E.M.) plasma ORAIP levels before and after (peak) stimulation were (16.4±9.6) and (55.2±34.2) ng/ml in N2/O2 inhalation, (14.1±12.4) and (34.3±14.6) ng/ml in cold/warm-stress, and (18.9±14.3) and (134.0±67.2) ng/ml in blood acidification study. These data strongly suggest that secretion of ORAIP in response to oxidative stress is universal mechanism and plays an essential role. ORAIP will be an important novel biomarker as well as a specific therapeutic target of these oxidative stress-induced cell injuries.
Highlights
Oxidative stress plays a pivotal role in ischaemia/reperfusion injury, atherosclerosis, aging and so on
We found that eukaryotic translation initiation factor 5A undergoes sulfation of 69th tyrosine residue in the trans-Golgi as well as more hypusination, and is rapidly secreted from cardiac myocytes in response to hypoxia/reoxygenation, induces apoptosis of the cells as a pro-apoptotic ligand [1]
We clearly showed for the first time that plasma levels of a novel oxidative stress-responsive apoptosis inducing protein (ORAIP) in rats subjected to three physicochemical models of oxidative stress were significantly increased within 30 min of stimulation
Summary
Oxidative stress plays a pivotal role in ischaemia/reperfusion injury, atherosclerosis, aging and so on. Using an in vitro model of myocardial ischaemia/reperfusion, we analysed the molecular mechanism involved in hypoxia/reoxygenation-induced apoptosis of cultured cardiac myocytes. We found that eukaryotic translation initiation factor 5A (eIF5A) undergoes sulfation of 69th tyrosine residue in the trans-Golgi as well as more hypusination, and is rapidly secreted from cardiac myocytes in response to hypoxia/reoxygenation, induces apoptosis of the cells as a pro-apoptotic ligand [1]. We refer to this novel posttranslationally modified secreted form of eIF5A, as oxidative stress-responsive apoptosis inducing protein (ORAIP).
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