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Sevoflurane postconditioning protects the myocardium against ischemia/reperfusion injury via activation of the JAK2 – STAT3 pathway

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ABSTRACT

Background: Sevoflurane postconditioning (S-post) has similar cardioprotective effects as ischemic preconditioning. However, the underlying mechanism of S-post has not been fully elucidated. Janus kinase signaling transduction/transcription activator (JAK2–STAT3) plays an important role in cardioprotection. The purpose of this study was to determine whether the cardioprotective effects of S-post are associated with activation of the JAK2–STAT3 signal pathway.

Methods: An adult male Sprague–Dawley (SD) rat model of myocardial ischemia/reperfusion (I/R) injury was established using the Langendorff isolated heart perfusion apparatus. At the beginning of reperfusion, 2.4% sevoflurane alone or in combination with AG490 (a JAK2 selective inhibitor) was used as a postconditioning treatment. The cardiac function indicators, myocardial infarct size, lactic dehydrogenase (LDH) release, mitochondrial ultrastructure, mitochondrial reactive oxygen species (ROS) generation rates, ATP content, protein expression of p-JAK, p-STAT3, Bcl-2 and Bax were measured.

Results: Compared with the I/R group, S-post significantly increased the expression of p-JAK, p-STAT3 and Bcl-2 and reduced the protein expression of Bax, which markedly decreased the myocardial infarction areas, improved the cardiac function indicators and the mitochondrial ultrastructure, decreased the mitochondrial ROS and increased the ATP content. However, the cardioprotective effects of S-post were abolished by treatment with a JAK2 selective inhibitor (p < 0.05).

Conclusion: This study demonstrates that the cardioprotective effects of S-post are associated with the activation of JAK2–STAT3. The mechanism may be related to an increased expression of p-JAK2 and p-STAT3 after S-post, which reduced mitochondrial ROS generation and increased mitochondrial ATP content, thereby reducing apoptosis and myocardial infarct size.

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S-post reduced mitochondrial ROS production.Mitochondrial ROS production rates (RPR) at the end of reperfusion. Data are presented as the mean ± SEM (n = 6/group). *p < 0.05 compared with sham group, #p < 0.05 compared with I/R group and &p < 0.05 compared with S-post group.
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fig-6: S-post reduced mitochondrial ROS production.Mitochondrial ROS production rates (RPR) at the end of reperfusion. Data are presented as the mean ± SEM (n = 6/group). *p < 0.05 compared with sham group, #p < 0.05 compared with I/R group and &p < 0.05 compared with S-post group.

Mentions: The mitochondrial ROS production rates in the I/R group were significantly higher than those in the Sham group. However, S-post significantly decreased the mitochondrial ROS production rates (p < 0.05, Fig. 6), and the mitochondrial ROS production rates were not significantly different among the AG490, S-post+AG490 and I/R groups after the application of the JAK2 selective inhibitor; no significant differences between the AG490 and S-post+AG490 groups were detected (p > 0.05, Fig. 6).


Sevoflurane postconditioning protects the myocardium against ischemia/reperfusion injury via activation of the JAK2 – STAT3 pathway
S-post reduced mitochondrial ROS production.Mitochondrial ROS production rates (RPR) at the end of reperfusion. Data are presented as the mean ± SEM (n = 6/group). *p < 0.05 compared with sham group, #p < 0.05 compared with I/R group and &p < 0.05 compared with S-post group.
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fig-6: S-post reduced mitochondrial ROS production.Mitochondrial ROS production rates (RPR) at the end of reperfusion. Data are presented as the mean ± SEM (n = 6/group). *p < 0.05 compared with sham group, #p < 0.05 compared with I/R group and &p < 0.05 compared with S-post group.
Mentions: The mitochondrial ROS production rates in the I/R group were significantly higher than those in the Sham group. However, S-post significantly decreased the mitochondrial ROS production rates (p < 0.05, Fig. 6), and the mitochondrial ROS production rates were not significantly different among the AG490, S-post+AG490 and I/R groups after the application of the JAK2 selective inhibitor; no significant differences between the AG490 and S-post+AG490 groups were detected (p > 0.05, Fig. 6).

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Background: Sevoflurane postconditioning (S-post) has similar cardioprotective effects as ischemic preconditioning. However, the underlying mechanism of S-post has not been fully elucidated. Janus kinase signaling transduction/transcription activator (JAK2&ndash;STAT3) plays an important role in cardioprotection. The purpose of this study was to determine whether the cardioprotective effects of S-post are associated with activation of the JAK2&ndash;STAT3 signal pathway.

Methods: An adult male Sprague&ndash;Dawley (SD) rat model of myocardial ischemia/reperfusion (I/R) injury was established using the Langendorff isolated heart perfusion apparatus. At the beginning of reperfusion, 2.4% sevoflurane alone or in combination with AG490 (a JAK2 selective inhibitor) was used as a postconditioning treatment. The cardiac function indicators, myocardial infarct size, lactic dehydrogenase (LDH) release, mitochondrial ultrastructure, mitochondrial reactive oxygen species (ROS) generation rates, ATP content, protein expression of p-JAK, p-STAT3, Bcl-2 and Bax were measured.

Results: Compared with the I/R group, S-post significantly increased the expression of p-JAK, p-STAT3 and Bcl-2 and reduced the protein expression of Bax, which markedly decreased the myocardial infarction areas, improved the cardiac function indicators and the mitochondrial ultrastructure, decreased the mitochondrial ROS and increased the ATP content. However, the cardioprotective effects of S-post were abolished by treatment with a JAK2 selective inhibitor (p &lt; 0.05).

Conclusion: This study demonstrates that the cardioprotective effects of S-post are associated with the activation of JAK2&ndash;STAT3. The mechanism may be related to an increased expression of p-JAK2 and p-STAT3 after S-post, which reduced mitochondrial ROS generation and increased mitochondrial ATP content, thereby reducing apoptosis and myocardial infarct size.

No MeSH data available.


Related in: MedlinePlus