Abstract
IntroductionAnesthetic-induced preconditioning (AIP) is known to elicit cardioprotective effects that are mediated at least in part by activation of the kinases AMPK and PKCε as well as by inhibition of JNK. Recent data demonstrated that the pleiotropic cytokine macrophage migration inhibitory factor (MIF) provides cardioprotection through activation and/or inhibition of kinases that are also known to mediate effects of AIP. Therefore, we hypothesized that MIF could play a key role in the AIP response.MethodsCardiomyocytes were isolated from rats and subjected to isoflurane preconditioning (4 h; 1.5 vol. %). Subsequently, MIF secretion and alterations in the activation levels of protective kinases were compared to a control group that was exposed to ambient air conditions. MIF secretion was quantified by ELISA and AIP-induced activation of protein kinases was assessed by Western blotting of cardiomyocyte lysates after isoflurane treatment.ResultsIn cardiomyocytes, preconditioning with isoflurane resulted in a significantly elevated secretion of MIF that followed a biphasic behavior (30 min vs. baseline: p = 0.020; 24 h vs. baseline p = 0.000). Moreover, quantitative polymerase chain reaction demonstrated a significant increase in MIF mRNA expression 8 h after AIP. Of note, activation of AMPK and PKCε coincided with the observed peaks in MIF secretion and differed significantly from baseline.ConclusionsThese results suggest that the pleiotropic mediator MIF is involved in anesthetic-induced preconditioning of cardiomyocytes through stimulation of the protective kinases AMPK and PKCε.
Highlights
Anesthetic-induced preconditioning (AIP) is known to elicit cardioprotective effects that are mediated at least in part by activation of the kinases AMPK and PKCe as well as by inhibition of Jun Nterminal kinase (JNK)
Preconditioning of the myocardium is known to elicit an overwhelming release of mediators that activate various cytoprotective pathways and confer protection against the deleterious sequelae of events in ischemia and reperfusion (I/R)
migration inhibitory factor (MIF) directly activates cardioprotective kinases Since MIF has repeatedly been shown to induce the activation of the protective kinase AMPK while inhibiting JNK [7,8], we investigated a potential association between the observed MIF secretion and kinase activation patterns after preconditioning with isoflurane
Summary
Anesthetic-induced preconditioning (AIP) is known to elicit cardioprotective effects that are mediated at least in part by activation of the kinases AMPK and PKCe as well as by inhibition of JNK. Preconditioning of the myocardium is known to elicit an overwhelming release of mediators that activate various cytoprotective pathways and confer protection against the deleterious sequelae of events in ischemia and reperfusion (I/R). This phenomenon typically consists of two distinct phases: the early phase which starts immediately after the termination of a preconditioning stimulus and which protects the myocardium for 2–3 h, and a late protection period occurring after 12–24 h, which lasts for 2–3 days. Inhibition of the opening of mitochondrial permeability pores (mPTPs) has been found to play a pivotal role in preconditioning-induced cardioprotection [3,6]
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