Overview

This dissertation, Remifentanil preconditioning reduces post-ischaemic myocardial infarction and improves left ventricular performance via activation of the JAK/STAT signal pathway and subsequent inhibition of GSK3β in rats by Yan, Wang, 王妍, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Remifentanil is an ultra-short-acting phenylpiperidine opioid analgesic that is rapidly metabolized by nonspecific blood and tissue esterases. In clinical practice, remifentanil is now more commonly used during both cardiac and non-cardiac surgery than classic opioid agonists such as morphine, since it can be given in higher doses, is more titratable and enables fast recovery of patients in the postoperative period. Remifentanil preconditioning (RPC), achieved by intravenous remifentanil infusion interspersed with infusion-free periods before indexed ischaemia, attenuates cardiac ischaemia-reperfusion injury (IRI). This is experimentally manifested by reduced postischaemic myocardial infarct size (IS) and diminished markers of cardiac failure and apoptosis, and, clinically, by reduced release of biomarkers of myocardial cellular injury after cardiac surgery. However, the underlying mechanisms by which RPC has a cardioprotective effect need to be further explored. It's generally considered that the Reperfusion Injury Salvage Kinase (RISK) pathway, triggering the expression of phosphatidylinositol 3-kinase (PI3K) as well as Akt, exerts a pivotal role in both classic ischaemic preconditioning (IPC) and pharmacological preconditioning induced cardioprotection. Moreover, recent studies show that the Survivor Activating Factor Enhancement (SAFE) signalling pathway, which involves signal transducers and activators of transcription-3 (STAT3) and janus activated kinase-2 (JAK2), also has an essential role in IPC. Although cross-talk has been found between the RISK and SAFE pathways, the SAFE pathway can function independently of the RISK to confer cardioprotection. However, the roles of JAK/STAT and PI3K/Akt signalling and, in particular, their relative importance in RPC-mediated cardioprotection have not been studied. I explored whether RPC confers cardioprotection via the JAK/STAT or PI3K/Akt pathway and its relationship with GSK3β inhibition. In first part of my study, I explored relative role of the JAK/STAT and PI3K/Akt which were involved in RPC cardioprotection using JAK2 and PI3K inhibition. Male Sprague-Dawley rats were either sham operated or randomly assigned to receive I/R alone or as well as RPC. Pretreatment with the JAK2 inhibitor AG490 or the PI3K inhibitor wortmannin was induced before ischaemia in rats. RPC reduced myocardial infarction and haemodynamic dysfunction induced by IRI accompanied with increased phosphorylation of STAT3 but not Akt or eNOS phosphorylation. AG490 but not wortmannin cancelled RPC's cardioprotection. In addition, RPC attenuated hypoxia/reoxygenation induced cardiomyocyte apoptosis while STAT3 knock-out abolished the protective effects of RPC. These findings suggest that RPC confers cardioprotection primarily via activation of the JAK/STAT signalling but not the PI3K/Akt signalling pathway. The second study further investigated the role of GSK3β in RPC cardioprotection using the GSK3β inhibitor SB216763. I found that SB restored the ability of RPC to reduce the extent of myocardial infarction and CK-MB release despite the presence of AG490. The phosphorylation of GSK3β was increased by RPC. In addition, GSK3β gene knock-out with siRNA preserved RPC's cardioprotection regardless of STAT3 abrogation indicating tha

Full Product Details

9781361362297

Table of Contents

Reviews

Author Information

Tab Content 6

Customer Reviews

Recent Reviews

Countries Available