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The Relationship between epigenetic factors and the anesthetic sevoflurane action

Grant number: 17/21306-1
Support Opportunities:Regular Research Grants
Duration: September 01, 2018 - August 31, 2020
Field of knowledge:Health Sciences - Medicine
Principal Investigator:José de Ribamar Costa Júnior
Grantee:José de Ribamar Costa Júnior
Host Institution: Instituto Dante Pazzanese de Cardiologia (IDPC). Fundação Adib Jatene (FAJ). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated researchers: Caetano Nigro Neto ; Mario Hiroyuki Hirata


Halogenated Inhalational anesthetics, including Sevoflurane, are widely used in cardiac surgeries because they present a cardioprotective effect. Several benefits have been attributed to Sevoflurane in different tissues and with different results. Since Sevoflurane has different actions to distant organs, the hypothesis of our study is that the anesthesic can act in a similar way to Myocardial Remote Ischemic Preconditioning by epigenetic regulation. In addition, the role of epigenetic variations in response to drugs, known as pharmacoepigenetic, is a mechanism that should be considered and may explain the intraoperative wake-up of some patients. Therefore, the aim of this study is to evaluate the relationship between the epigenetic factors and the effects of Sevoflurane in two different situations: (1) In the anti-inflammatory response during CPB in cardiac surgery; (2) In the patient's response to Sevoflurane at different doses. In both situations, patients will be randomized into two groups: SEVO (using sevoflurane in the CPB period) and CONTROL (without sevoflurane use in the CPB period). Blood samples will be collected for gene and miRNA expression and DNA methylation analysis and to determine the plasma inflammatory markers concentration. The plasma concentration of IL-1², IL-6, IL-8, IL-10, IL-4, TNF±, TGF² and PMN-elastase will be determined using the Luminex100TM detection system (Luminex). The mRNA quantification of IL1B, IL6, IL8, IL10, IL4, TN4, TNFA, TGFB1, ELANE, RYR1 and of genes encoding the GABA and nAChR subunits (nicotinic type cholinergic receptor) will be performed by real time PCR using the TaqMan® Gene Expression Assay detection system (Applied Biosystems). For miRNA expression analysis, the Ingenuity® Pathway Analysis (IPA®) platform (Qiagen) will be used for the selection of miRNAs that regulate the genes differentially expressed between the groups. Expression of miRNA will be analyzed by real-time PCR using the TaqMan® MicroRNA Assays detection system (Applied Biosystems). PCR results will be analyzed using the Rotor-Gene Q-Pure detection software (Qiagen). For DNA methylation, the CpG islands in the promoter region from genes above will be analyzed by pyrosequencing. The bisulfite DNA conversion will be performed using the EpiTect Fast DNA Bisulfite Conversion Kit (Qiagen). The converted DNA will be amplified using the the PyroMark PCR Kit (Qiagen) and the PyroMark CpG Assays (Qiagen). The purification and denaturation of PCR product will be performed using the PyroMark Vacuum Workstation (Qiagen) while the sequencing reaction will be performed using the PyroMark Q24 platform (Qiagen). Taking into account all clinical effects associated with Sevoflurane and the potential role of epigenetic on its long-distance mechanism action and on the patient's drug response, a better understanding of the relationship between the epigenetic factors and the effects of Sevoflurane is a great promise for the development of prophylactic, diagnostic and therapeutic tools which can improve the management of the cardiac patient. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
AZEVEDO MARANHAO CARDOSO, THIAGO AUGUSTO; KUNST, GUDRUN; NETO, CAETANO NIGRO; COSTA JUNIOR, JOSE DE RIBAMAR; SANTOS SILVA, CARLOS GUSTAVO; BASTOS, GISELE MEDEIROS; BORGES, JESSICA BASSANI; HIRATA, MARIO HIROYUKI. Effect of sevoflurane on the inflammatory response during cardiopulmonary bypass in cardiac surgery: the study protocol for a randomized controlled trial. Trials, v. 22, n. 1, . (17/21306-1)

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