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Comparative Study
, 144 (1), 123-32

The Noble Gas Xenon Induces Pharmacological Preconditioning in the Rat Heart in Vivo via Induction of PKC-epsilon and p38 MAPK

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Comparative Study

The Noble Gas Xenon Induces Pharmacological Preconditioning in the Rat Heart in Vivo via Induction of PKC-epsilon and p38 MAPK

Nina C Weber et al. Br J Pharmacol.

Abstract

Xenon is an anesthetic with minimal hemodynamic side effects, making it an ideal agent for cardiocompromised patients. We investigated if xenon induces pharmacological preconditioning (PC) of the rat heart and elucidated the underlying molecular mechanisms. For infarct size measurements, anesthetized rats were subjected to 25 min of coronary artery occlusion followed by 120 min of reperfusion. Rats received either the anesthetic gas xenon, the volatile anesthetic isoflurane or as positive control ischemic preconditioning (IPC) during three 5-min periods before 25-min ischemia. Control animals remained untreated for 45 min. To investigate the involvement of protein kinase C (PKC) and p38 mitogen-activated protein kinase (MAPK), rats were pretreated with the PKC inhibitor calphostin C (0.1 mg kg(-1)) or the p38 MAPK inhibitor SB203580 (1 mg kg(-1)). Additional hearts were excised for Western blot and immunohistochemistry. Infarct size was reduced from 50.9+/-16.7% in controls to 28.1+/-10.3% in xenon, 28.6+/-9.9% in isoflurane and to 28.5+/-5.4% in IPC hearts. Both, calphostin C and SB203580, abolished the observed cardioprotection after xenon and isoflurane administration but not after IPC. Immunofluorescence staining and Western blot assay revealed an increased phosphorylation and translocation of PKC-epsilon in xenon treated hearts. This effect could be blocked by calphostin C but not by SB203580. Moreover, the phosphorylation of p38 MAPK was induced by xenon and this effect was blocked by calphostin C. In summary, we demonstrate that xenon induces cardioprotection by PC and that activation of PKC-epsilon and its downstream target p38 MAPK are central molecular mechanisms involved. Thus, the results of the present study may contribute to elucidate the beneficial cardioprotective effects of this anesthetic gas.

Figures

Figure 1
Figure 1
(a) Experimental protocol-anesthetic preconditioning. Xe=xenon, Iso=isoflurane, PC=preconditioning, Occ=coronary artery occlusion. (b) Experimental protocol-ischemic preconditioning (IPC).
Figure 2
Figure 2
(a) Infarct size-anesthetic preconditioning. Histogram shows the infarct size (percent of area at risk) of controls, xenon (Xe-PC), isoflurane-preconditioning (Iso-PC), calphostin C alone, Xe-PC and Iso-PC+calphostin C, SB203580 alone, Xe-PC and Iso-PC+SB203580 group. Data show means±s.d., *P<0.05 vs control group, P<0.05 vs Xe-PC, P<0.05 vs Iso-PC. (b) Infarct size-ischemic preconditioning. Histogram shows the infarct size (percent of area at risk) of controls, ischemic preconditioning (IPC), IPC+calphostin C and IPC+SB203580 group. Data show means±s.d., *P<0.05 vs control group.
Figure 3
Figure 3
(a) Phosphorylation of PKC-ɛ in anesthetic preconditioning. One representative Western blot experiment of cytosolic fraction of control and xenon or isoflurane treated hearts in the presence or absence of calphostin C and SB203580 (each n=6) is shown. Upper panel shows phosphorylated form of PKC-ɛ, and lower panel total PKC-ɛ. The histogram presents densitometric evaluation as x-fold average light intensity (AVI). Data show ratio of phosphorylated vs total PKC-ɛ (means±s.d.). *P<0.05 vs control, P<0.05 vs Xe-PC and P<0.05 vs Iso-PC. (b) Phosphorylation of PKC-ɛ in ischemic preconditioning. One representative Western blot experiment of cytosolic fraction of control and IPC treated hearts in the presence or absence of calphostin C and SB203580 (each n=6) is shown. Upper panel shows phosphorylated form of PKC-ɛ, and lower panel total PKC-ɛ. The histogram presents densitometric evaluation as x-fold average light intensity (AVI). Data show ratio of phosphorylated vs total PKC-ɛ (means±s.d.).
Figure 4
Figure 4
(a) Subcellular distribution of PKC-ɛ. Slides show immunofluorescence staining experiment. Cryocuts of control (left panel), xenon treated (middle panel) or isoflurane treated (right panel) hearts were stained for PKC-ɛ. Stained sections are visualized using a fluorescence microscope 630-fold magnification (excitation: 554 nm; emission: 573 nm). (b) Translocation of PKC-ɛ. Membrane (right panel) and cytosolic (left panel) fraction of control, xenon and isoflurane hearts (each n=6) were immunoblotted using antibodies against PKC-ɛ (upper panel) or α-tubulin (lower panel). α-Tubulin was used as standard in order to test for uniform protein distribution on the blot. One representative Western blot experiment is shown. The histogram presents densitometric evaluation as x-fold average light intensity (AVI). Data show means±s.d. *P<0.05 vs control.
Figure 5
Figure 5
(a) Phosphorylation of p38 MAPK – causal relationship between PKC and p38 MAPK anesthetic preconditioning. One representative Western blot experiment of cytosolic fraction of control, xenon or isoflurane treated hearts in the presence or absence of calphostin C (each, n=6) is shown. Upper panel shows phosphorylated form of p38 MAPK, lower panel total p38 MAPK. The histogram presents densitometric evaluation as x-fold average light intensity (AVI). Data show ratio of phosphorylated vs total p38 MAPK (means±s.d.). *P<0.05 vs control, P<0.05 vs Xe-PC and P<0.05 vs Iso-PC. (b) Phosphorylation of p38 MAPK – causal relationship between PKC and p38 MAPK ischemic preconditioning. One representative Western blot experiment of cytosolic fraction of control, IPC treated hearts in the presence or absence of calphostin C (each, n=6) is shown. Upper panel shows phosphorylated form of p38 MAPK, lower panel total p38 MAPK. The histogram presents densitometric evaluation as x-fold average light intensity (AVI). Data show ratio of phosphorylated vs total p38 MAPK (means±s.d.).

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