title: Dexmedetomidine preconditioning for myocardial protection in ischaemia-reperfusion injury in rats by downregulation of the high mobility group box 1-toll-like receptor 4-nuclear factor κB signalling pathway.
abstract: Pharmacological preconditioning reduces myocardial infarct size in ischaemia-reperfusion (I-R) injury. Dexmedetomidine, a selective α2-adrenoceptor agonist, has a proven cardioprotective effect when administered prior to I-R, although the underlying mechanisms for this effect are not fully understood. We evaluated whether dexmedetomidine preconditioning could induce a myocardio-protective effect against I-R injury by inhibiting associated inflammatory processes through downregulation of the high mobility group box 1 (HMGB1)-toll-like receptor 4 (TLR4)-nuclear factor κB (NF-κB) signalling pathway. Seventy rats were randomly assigned to seven groups: a control and six test groups, involving I-R for 30 and 120 minutes, respectively, in isolated rat hearts and different pretreatment protocols with dexmedetomidine (10 nmol/L) as well as yohimbine (1 μmol/L) and recombinant HMGB1 peptide (rHMGB1; 20 μg/L), alone or in combination with dexmedetomidine. Cardiac function was recorded; myocardial HMGB1, TLR4, and NF-κB activities and levels of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured as were lactate dehydrogenase (LDH) and creatine kinase (CK) in coronary outflow. Dexmedetomidine preconditioning significantly improved cardiac function (P<.05), downregulated the expression of HMGB1-TLR4-NF-κB, reduced levels of TNF-α and IL-6 in isolated ventricles during I-R injury, and significantly reduced CK and LDH levels in coronary outflow (P<.05). All of these effects were partially reversed by yohimbine (P<.05) or rHMGB1 (P<.05). Dexmedetomidine preconditioning alleviated myocardial I-R injury in rats through inhibition of inflammatory processes associated with downregulation of the HMGB1-TLR4-NF-κB signalling pathway via activation at α2-adrenergic receptors.
authors.affiliation: Department of Anaesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Yu-Fan
authors.initials: YF
authors.lastname: Yang
authors.affiliation: Department of Anaesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Peng
authors.affiliation: Department of Anaesthesiology and Pain Medicine, University of California Davis Health System, Sacramento, CA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Anaesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Xiao-Wen
authors.initials: XW
authors.lastname: Meng
authors.affiliation: Department of Anaesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Zhang
authors.affiliation: Department of Anaesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Fu-Hai
authors.initials: FH
authors.lastname: Ji
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D020927:Dexmedetomidine / Q000008:administration & dosage* / Q000627:therapeutic use*; D024243:HMGB1 Protein / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D024243:HMGB1 Protein; D016328:NF-kappa B; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D020927:Dexmedetomidine
keywords: dexmedetomidine; high mobility group box 1-toll-like receptor 4-nuclear factor κB; myocardial protection; preconditioning