http://www.sciencedirect.com/science/article/pii/S1874391913004582
- a School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
- b Choju Medical Institute, Fukushimura Hospital, Toyohashi, Aichi 441-8124, Japan
- c Graduate School of Biomedical Science and Engineering, Hanyang University, Seongdong-gu, Seoul 133-791, Republic of Korea
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View full textHighlights
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- Identification of human ischemic proteome (1520 proteins, FDR = 0.1%) by iTRAQ
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- Global failure of the cellular energy metabolism in the ischemic infarcts
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- Concomitant reduction of all participating proteins of the malate-aspartate shuttle
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- Iron-mediated oxidative imbalance as seen by the elevation of ferritin
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- Presence of reactive gliosis along with an increased anti-inflammatory response
Abstract
Ischemic
stroke, still lacking an effective neuroprotective therapy is the third
leading cause of global mortality and morbidity. Here, we have applied
an 8-plex iTRAQ-based 2D-LC-MS/MS strategy to study the commonly
regulated infarct proteome from three different brain regions (putamen,
thalamus and the parietal lobe) of female Japanese patients. Infarcts
were compared with age-, post-mortem interval- and location-matched
control specimens.
The iTRAQ experiment confidently
identified 1520 proteins with 0.1% false discovery rate. Bioinformatic
data mining and immunochemical validation of pivotal perturbed proteins
revealed a global failure of the cellular energy metabolism in the
infarcted tissues as seen by the parallel down-regulation of proteins
related to glycolysis, pyruvate dehydrogenase complex, TCA cycle and
oxidative phosphorylation. The concomitant down-regulation of all
participating proteins (SLC25A11, SLC25A12, GOT2 and MDH2) of
malate-aspartate shuttle might be responsible for the metabolic
in-coordination between the cytosol and mitochondria resulting in the
failure of energy metabolism. The levels of proteins related to reactive
gliosis (VIM, GFAP) and anti-inflammatory response (ANXA1, ANXA2)
showed an increasing trend. The elevation of ferritin (FTL, FTH1) may
indicate an iron-mediated oxidative imbalance aggravating the
mitochondrial failure and neurotoxicity. The deregulated proteins could
be useful as potential therapeutic targets or biomarkers for ischemic
stroke.
Biological Significance
Clinical
proteomics of stroke has been lagging behind other areas of clinical
proteomics like Alzhemer’s Disease or Schizophrenia. Our study is the
first quantitative clinical proteomics study where iTRAQ-2D-LC-MS/MS has
been utilized in the area of ischemic stroke to obtain a comparative
profile of human ischemic infarcts and age-, sex-, location- and
post-mortem interval-matched control brain specimens. Different
pathological attributes of ischemic stroke well-known through basic and
pre-clinical research such as failure of cellular energy metabolism,
reactive gliosis, activation of anti-inflammatory response and aberrant
iron metabolism have been observed at the bedside. Our dataset could act
as a reference for similar studies done in the future using ischemic
brain samples from various brain banks across the world. Meta-analysis
of these studies in the future could help to map the pathological
proteome specific to ischemic stroke that will guide the scientific
community to better evaluate the pros and cons of the pre-clinical
models for efficacy and mechanistic studies.
Infarct
being the core of injury should have the most intense regulation for
several key proteins involved in the pathophysiology of ischemic stroke.
Hence, a part of the up-regulated proteome could leak into the general
circulation that may offer candidates of interest as potential
biomarkers. In support of our proposed hypothesis, we report ferritin in
the current study as one of the most elevated protein in the infarct,
which has been documented as a biomarker in the context of ischemic
stroke by an independent study. Overall, our approach has the potential
to identify probable therapeutic targets and biomarkers in the area of
ischemic stroke.
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