Berberine Protects The Heart From Ischemia Reperfusion Injury By Attenuating Endoplasmic Reticulum Stress Via JAK2/STAT3 Signaling Pathway

Objective To determine whether BBR protects against MI/R injury by attenuating ER stress-induced apoptosis and the role of JAK2/STAT3 signaling in this process.Methods First we tested the effects of BBR and AG490 on MI/R-injured rat hearts. The experiments were conducted as follows(n = 8): 1) MI/R+V group: normal rats were orally gavaged with 0.5% CMC-Na solution(2 ml/d) for 2 weeks and then received MI/R operation; 2) MI/R+BBR group: normal rats were orally treated with BBR as described above and then received MI/R operation; 3) MI/R+BBR+AG: normal rats were treated with BBR as well as AG490 as described above, and then received MI/R operation; 4) MI/R+AG: normal rats were treated with AG490 alone as described before and then received MI/R operation. Then we determined the role of JAK2/STAT3 signaling in BBR's protective effect in cultured H9C2 cells. We chose 50 ?mol as the experimental concentration based on our preliminary experiment and the previous reports. After preparation, the cells were divided into the following groups(8 separate experiments were performed in each experimental condition): 1) Simulated ischemia/reperfusion(SIR) group: the cardiomyocytes were incubated in normal DMEM for 28 h, subjected to simulated ischemia for 2 h, and then incubated in normal DMEM for 4 h to simulate reperfusion; 2) SIR+BBR group: the cardiomyocytes were incubated in normal DMEM for 24 h, incubated in DMEM with 50 ?mol BBR for 4 h, and then subjected to SIR treatment; 3) SIR+BBR+JAK2 si RNA group: after the cells were transfected with JAK2 si RNA, cells were treated with 50 ?mol BBR for 4 h and then exposed to SIR injury. 4) SIR+JAK2 si RNA: the cardiomyocytes were transfected with JAK2 si RNA and then exposed to SIR injury.Results In vivo MI/R injury significantly impaired cardiac function, increased myocardial apoptosis, oxidative damage and ER stress level. BBR treatment effectively reduced myocardial apoptosis, infarct size, oxidative damage and ER stress induced by PERK/e IF2?/ATF4 signaling, thus improved myocardial function. Furthermore, BBR significantly activated JAK2/STAT3 signaling and inhibiting with AG490(the inhibitor of JAK2/STAT3 signaling) blocked BBR's protective effects. BBR also markedly reduced cardiac apoptosis, oxidative stress and ER stress induced by SIR treatment in H9C2 cells. Consistently, these effects were abolished by JAK2 si RNA administration.Conclusion We demonstrate that BBR ameliorates MI/R injury by attenuating endoplasmic reticulum stress-induced apoptosis via JAK2/STAT3 signaling pathway.