Identification Of Sevoflurane And Propofol Induced Gene Expression Changes With DNA Microarray

Coronary artery bypass grafting (CABG) surgery is one of the common cardiac surgical procedures. The CABG surgery can be performed with and without cardiopulmonary bypass, referred to as on-pump CABG (traditional way) and off-pump CABG (innovative way), respectively. Many studies have confirmed that compared with the on-pump CABG, off-pump CABG has lower risk of renal damage, myocardial injury, injury to the brain, stroke, atrial fibrillation neurocognitive and organ dysfunction. The CABG surgery could lead to ischemic injury since there is a transient period of local ischemia with temporary occlusion of the target vessel, especially for patients with poor cardiac contractile function. Some cytokines, such as interleukin (IL)-6, interferon-y, high sensitivity C-reactive protein and granulocyte colony-stimulating factor, were observed released in off-pump CABG surgery to a similar or even larger extent with on-pump CABG surgery. Therefore, perioperative management for off-pump CABG surgery needs to be improved by the reduction in myocardial ischemia-reperfusion damage.Application of interventions, such as certain anesthetic agents, before and after myocardial ischaemia could reduce the myocardial ischemic damage and subsequent reperfusion injury at some extent. Sevoflurane is a kind of inhalational anaesthetic agents which could significantly reduce the infarct size and Ca2+loading to protect myocardium against reperfusion injury. It has been reported that preconditioning by sevoflurane could down-regulate platelet-endothelial cell adhesion molecule-1(PECAM-1/CD31) and up-regulate catalase in the atrial biopsies from patients undergoing CABG surgery. The serum IL-6and IL-8could be suppressed by sevoflurane, while the IL-10and IL-1receptor antagonist (IL-lra) still significantly increased in patients undergoing CABG. Aside from volatile anesthetics, intravenous anesthetics such as propofol also could reduce the myocardial reperfusion injury for patients undergoing CABG surgery. It has been reported that propofol could reduce the lipid peroxidation mediated by free radicals and systemic inflammation for patients with impaired left ventricular function undergoing CABG surgery. The activities of nitric oxide synthase (NOS) and phosphoinositide-3-kinase/Akt maintained by propofol might be partly responsible for reduced ischemia-reperfusion injury. Accumulated evidences have shown that sevoflurane and propofol have effective cardioprotective effects, while the underlying mechanisms of these anaesthetic agents for cardioprotection still remain unclear. In this current study, we firstly identified common differentially expressed genes (DEGs), propofol specific DEGs and sevoflurane specific DEGs. Then, not only functional annotation for the DEGs (common DEGs, propofol specific DEGs and sevoflurane specific DEGs) but also functional analysis for the DEGs (common DEGs, propofol specific DEGs and sevoflurane specific DEGs) in the selected interactive functional modules were performed. We anticipate that the results of our study could reveal some novel mechanisms about the cardioprotective effects of sevoflurane and propofol. The results of our studies were as follows:1. The normalized expression profiles were analyzed to identify DEGs with FDR<0.05and|logFC|>1. Total879and290DEGs were selected in the sevoflurane group and propofol group, respectively.2. The DEGs in the sevoflurane group were compared with the DEGs in the propofol group. There were275common DEGs,604sevoflurane specific DEGs and15propofol specific DEGs, respectively. The differences in the expression levels were in accordance with the DEGs identification. The sevoflurane specific DEGs were differentially expressed in the sevoflurane group (P=0.01239) other than in the propofol group (P=0.214). Meanwhile, the propofol specific DEGs were differentially expressed in the propofol group (P=0.02206) other than in the sevoflurane group (P=0.2243). Furthermore, the common DEGs were differentially expressed in the sevoflurane group (P=2.2e-16) and propofol group (P=2.98e-14).3. The function of response to wounding involving72DEGs was the most significant GO Term for the879DEGs in the sevoflurane group and response to organic substance involving45DEGs was the most significant GO Term for290DEGs in the propofol group. The common DEGs, sevoflurane specific DEGs and propofol specific DEGs were analyzed by comparing with COG database with the E-value<le-05, respectively. The results showed that the functional categories in CC, MF and BP for the common DEGs, sevoflurane specific DEGs and propofol specific DEGs were very similar.4. Total2,1, and1function modules for the common DEGs, propofol specific DEGs and sevoflurane specific DEGs were respectively identified with the FDR<0.05. There were10and18DEGs in the two function modules for the common DEGs, such as ATF3(activating transcription factor3), JUND (jun D proto-oncogene), MAP2K3 (mitogen-activated protein kinase kinase3), FOSB (FBJ murine osteosarcoma viral oncogene homolog B), JUNB (jun B proto-oncogene) and TNFAIP3(tumor necrosis factor, alpha-induced protein3). Total2up-regulated DEGs including CD93and leucine rich repeat containing32(LRRC32) were involved in the function modules for propofol specific DEGs. Eight up-regulated DEGs, such as CISH (cytokine inducible SH2-containing protein), PTPN1(protein tyrosine phosphatase, non-receptor type1), SOCS1(suppressor of cytokine signaling1), IL15RA (interleukin15receptor, alpha), RCAN1(regulator of calcineurin1), IL6R (interleukin6receptor), DUSP4(dual specificity phosphatase4) and STAT3(signal transducer and activator of transcription3) involved in the function modules for sevoflurane specific DEGs. Meanwhile,7down-regulated DEGs including CPXM1(carboxypeptidase X (M14family), member1), FGFR2(fibroblast growth factor receptor2), FLRT3(fibronectin leucine rich transmembrane protein3), IL17RD (interleukin17receptor D), IRS1(insulin receptor substrate1), IL7, CSF1R (colony stimulating factor1receptor) were also contained in the function modules for sevoflurane specific DEGs. The DEGs in the modules participate in the cellular processes, such as regulation of transcription and regulation of cellular process, which were similar with the functional annotations for the DEGs.In conclusion, sevoflurane and propofol may synergistically reduce the myocardial reperfusion injury for the patients undergoing CABG surgery since expression changes induced by sevoflurane or propofol tend to be similar. However, the underlying molecular mechanisms of anesthetic agents for cardioprotection still need to be further studied and confirmed by experiments.