Whole blood transcriptomics in cardiac surgery identifies a gene regulatory network connecting ischemia reperfusion with systemic inflammation.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
The Kidney and Dialysis Research Laboratory, Division of Nephrology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts, United States of America. liangos_o@hotmail.com
Orfeas
O
Liangos
Sophie
S
Domhan
Christian
C
Schwager
Martin
M
Zeier
Peter E
PE
Huber
Francesco
F
Addabbo
Michael S
MS
Goligorsky
Lynn
L
Hlatky
Bertrand L
BL
Jaber
Amir
A
Abdollahi
D001798:Blood Proteins / Q000235:genetics*; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D011446:Prospective Studies; D015427:Reperfusion Injury / Q000097:blood / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood / Q000235:genetics*; D019616:Thoracic Surgical Procedures
D001798:Blood Proteins