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 α -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 α -adrenergic receptors.

Dexmedetomidine post‐treatment attenuates cardiac ischaemia/reperfusion injury by inhibiting apoptosis through HIF‐1α signalling

“…First, we did not conduct cardiac‐function tests to investigate the beneficial role of DEX in rats. Nevertheless, our recent study has shown that DEX improved cardiac function in isolated hearts during I/R injury . Next, no survival benefit of DEX was shown in our animals.…”

“…However, our findings on cardiomyocytes suggest that DEX may directly act on the cells. Recently, our studies showed that DEX pre‐treatment attenuated I/R‐induced cardiac injury by inhibiting inflammation . In addition to its cardioprotective benefits, DEX has been found to attenuate I/R injury in other vital organs, including the brain, liver, kidney, lungs and spinal cord …”

“…Our previous study suggested that DEX use during cardiac surgery was correlated with a lower post‐operative mortality rate and fewer complications . Animal studies showed that DEX pre‐treatment attenuated myocardial I/R injury, in part, by inhibiting inflammatory responses …”

“…10 Animal studies showed that DEX pre-treatment attenuated myocardial I/R injury, in part, by inhibiting inflammatory responses. 11,12 Compared with pre-treatment, DEX administration at the onset of reperfusion (post-treatment) is more applicable in clinical practice. However, the underlying mechanism of DEX post-treatment during cardiac I/R injury is unclear.…”

Dexmedetomidine Protects Mouse Brain from Ischemia-Reperfusion Injury via Inhibiting Neuronal Autophagy through Up-Regulating HIF-1α

“…Some of DEX-induced neuroprotective functions are mediated via the α 2 -adrenoceptor subtypes (Ma et al, 2004). In addition, some studies have reported that DEX preconditioning effectively reduces the inflammatory response of myocardial, renal and spinal cord ischemia by downregulation of high-mobility group protein B1 (HMGB1)/toll-like receptor 4 (TLR4) pathways (Gu et al, 2011; Rong et al, 2017; Yang et al, 2017). Meanwhile, DEX has been reported being protective in brain, intestinal, renal and lung by inhibiting apoptosis, necrosis (Engelhard et al, 2003; Gencer et al, 2014; Cui et al, 2015; Sun et al, 2015) and inhibition of autophagy in lung and kidney ischemic reperfusion injury (Lempiäinen et al, 2014; Xie et al, 2015).…”