Remote Limb Ischaemic Postconditioning Protects Against Myocardial Ischaemia/Reperfusion Injury in Mice: Activation of JAK/STAT3-Mediated Nrf2-Antioxidant Signalling.

Abstract

BACKGROUND:

This study aimed to evaluate the protective effect and mechanisms of remote limb ischaemic postconditioning (RIPostC) against myocardial ischaemia/reperfusion (IR) injury.

METHODS:

Male mice underwent 45 min of coronary artery occlusion followed by 2 h of reperfusion. RIPostC was achieved by three cycles of 5 min of ischaemia and 5 min of reperfusion in the left hind limb at the start of the reperfusion period. After 2 h of cardiac reperfusion, myocardial infarct size, cardiac enzyme release, apoptosis and oxidative stress were assessed. Protein expression and phosphorylation were measured by Western blotting.

RESULTS:

RIPostC significantly decreased cardiac IR injury, as reflected by reduced infarct size and cellular apoptosis (22.9 ± 3.3% vs 40.9 ± 6.2% and 13.4% ± 3.1% vs 26.2% ± 3.1%, respectively, both P < 0.01) as well as plasma creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) release (21.97 ± 4.08 vs 35.86 ± 2.91 ng/ml and 6.17 ± 0.58 vs 8.37 ± 0.89 U/ml, respectively, both P < 0.01) compared with the IR group. RIPostC significantly increased the phosphorylation of myocardial STAT3, Akt and eNOS (P < 0.01). In addition, RIPostC elevated the nuclear translocation of Nrf2 and the expression of HO-1 and reduced myocardial oxidative stress (P < 0.05). Interestingly, pretreatment with the JAK/STAT3 inhibitor AG490 blocked the cardioprotective effect of RIPostC accompanied by decreased phosphorylation of myocardial STAT3, Akt and eNOS (P < 0.05), decreased nuclear translocation of Nrf2 and expression of HO-1, as well as increased oxidative stress (P < 0.05).

CONCLUSION:

RIPostC attenuates apoptosis and protects against myocardial IR injury, possibly through the activation of JAK/STAT3-mediated Nrf2-antioxidant signalling.

• Authors: Sumin Gao, Leyun Zhan, Zhengchao Yang, Ruili Shi, Haobo Li, Zhengyuan Xia, Shiying Yuan, Qing-Ping Wu, Tingting Wang, Shanglong Yao
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 43 Issue 3 Pg. 1140-1151 ( 2017) ISSN: 1421-9778 [Electronic] Germany
• PMID: 28977786 (Publication Type: Journal Article)
• Copyright: © 2017 The Author(s). Published by S. Karger AG, Basel.

Chemical References

• Antioxidants
• NF-E2-Related Factor 2
• STAT3 Transcription Factor
• Tyrphostins
• alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
• Superoxides
• L-Lactate Dehydrogenase
• Nitric Oxide Synthase Type III
• Proto-Oncogene Proteins c-akt
• Creatine Kinase, MB Form

Topics

• Animals
• Antioxidants (metabolism)
• Apoptosis (drug effects)
• Coronary Vessels (physiology)
• Creatine Kinase, MB Form (blood)
• Disease Models, Animal
• Ischemic Postconditioning
• L-Lactate Dehydrogenase (blood)
• Male
• Mice
• Mice, Inbred C57BL
• Myocardial Reperfusion Injury (metabolism, pathology, prevention & control)
• NF-E2-Related Factor 2 (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Oxidative Stress (drug effects)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Superoxides (analysis)
• Tyrphostins (pharmacology)