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.

The induction of ferroptosis by impairing STAT3/Nrf2/GPx4 signaling enhances the sensitivity of osteosarcoma cells to cisplatin

“…STAT3 is activated in response to cisplatin and mediates cisplatin resistance in multiple cancers. There are reports that STAT3 enhances antioxidant capacity of cells by activating nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates the expression of various antioxidant proteins, thus protecting against oxidative damage (Gao et al, 2017). This evidence supports the hypothesis that STAT3/Nrf2 signaling might have implications in the regulation of ferroptosis.…”

Repeated Non-Invasive Limb Ischemic Preconditioning Confers Cardioprotection Through PKC-Ԑ/STAT3 Signaling in Diabetic Rats

“…It is interesting to note that STAT3 is not only important for the cardioprotection mediated by ischemic and remote ischemic preconditioning [14, 46] but is also critical in postconditioning cardioprotection [47, 48]. Reduced levels of STAT3 protein in the aged hearts of rodents may be responsible for the loss of cardioprotection by preconditioning and postconditioning [47].…”

Deletion of Rap1 protects against myocardial ischemia/reperfusion injury through suppressing cell apoptosis via activation of STAT3 signaling

“…As an essential component of the survivor activating factor enhancement pathway, activation of STAT3 signaling has been implicated in protecting the heart from myocardial I/R injury under both ischemic pre-or post-conditioning protocols and basal conditions. [32][33][34][35] Mice with cardiac-specific knockout of STAT3 develop significantly greater myocardial IS within the left ventricle, which is associated with increased cardiac apoptosis, reduced cardiac function, and reduced survival. 36 In contrast, cardiac-specific transgenic mice expressing STAT3 exhibit reduced myocardial IS and cardiomyocyte apoptosis when compared with non-transgenic littermates.…”