PloS one, 2010-10, Vol.5 (10), p.e13658-e13658
2010
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- Autor(en) / Beteiligte
- Titel
- Whole blood transcriptomics in cardiac surgery identifies a gene regulatory network connecting ischemia reperfusion with systemic inflammation
- Ist Teil von
- PloS one, 2010-10, Vol.5 (10), p.e13658-e13658
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2010
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Cardiac surgery with cardiopulmonary bypass (CS/CPB) is associated with increased risk for postoperative complications causing substantial morbidity and mortality. To identify the molecular mechanisms underlying CS/CPB-induced pathophysiology we employed an integrative systems biology approach using the whole blood transcriptome as the sentinel organ. Total RNA was isolated and globin mRNA depleted from whole blood samples prospectively collected from 10 patients at time points prior (0), 2 and 24 hours following CS/CPB. Genome-wide transcriptional analysis revealed differential expression of 610 genes after CS/CPB (p<0.01). Among the 375 CS/CPB-upregulated genes, we found a gene-regulatory network consisting of 50 genes, reminiscent of activation of a coordinated genetic program triggered by CS/CPB. Intriguingly, the highly connected hub nodes of the identified network included key sensors of ischemia-reperfusion (HIF-1alpha and C/EBPbeta). Activation of this network initiated a concerted inflammatory response via upregulation of TLR-4/5, IL1R2/IL1RAP, IL6, IL18/IL18R1/IL18RAP, MMP9, HGF/HGFR, CalgranulinA/B, and coagulation factors F5/F12 among others. Differential regulation of 13 candidate genes including novel, not hitherto CS/CBP-associated genes, such as PTX3, PGK1 and Resistin, was confirmed using real-time quantitative RT-PCR. In support of the mRNA data, differential expression of MMP9, MIP1alpha and MIP1beta plasma proteins was further confirmed in 34 additional patients. Analysis of blood transcriptome uncovered critical signaling pathways governing the CS/CPB-induced pathophysiology. The molecular signaling underlying ischemia reperfusion and inflammatory response is highly intertwined and includes pro-inflammatory as well as cardioprotective elements. The herein identified candidate genes and pathways may provide promising prognostic biomarker and therapeutic targets.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0013658Titel-ID: cdi_plos_journals_1292582073
- Format
- –
- Schlagworte
- Activation, Analysis, Bioindicators, Biology, Biomarkers, Blood, Blood proteins, Blood Proteins - genetics, Cancer, Cell Biology/Cellular Death and Stress Responses, Clinical outcomes, Coagulation, Complications, Conditioned stimulus, Coronary artery bypass, Critical Care and Emergency Medicine/Perioperative Critical Care, Diabetes, Gelatinase B, Gene expression, Gene Expression Profiling, Gene regulation, Gene Regulatory Networks, Genes, Genetic aspects, Genetics and Genomics/Gene Expression, Genomes, Genomics, Health aspects, Heart, Heart attacks, Heart diseases, Heart surgery, Hemodialysis, Humans, Hypoxia, Hypoxia-inducible factor 1a, Inflammation, Inflammatory response, Insulin resistance, Interleukin 1, Interleukin 18, Interleukin 6, Ischemia, Laboratories, Lungs, Medical research, Medical schools, Medicine, Molecular modelling, Morbidity, Mortality, Oncology, Pathways, Patients, Physicians, Physiology/Cell Signaling, Plasma proteins, Polymerase chain reaction, Prospective Studies, Proteins, Reperfusion, Reperfusion Injury - blood, Reperfusion Injury - genetics, Reverse Transcriptase Polymerase Chain Reaction, Ribonucleic acid, RNA, Rodents, Signal transduction, Signaling, Stem cells, Studies, Surgery, Surgery/Cardiothoracic Surgery, Systemic Inflammatory Response Syndrome - blood, Systemic Inflammatory Response Syndrome - genetics, Thoracic Surgical Procedures, Transcription, Transcription (Genetics), Transcription activation, Transplants & implants, Veins & arteries