Aim: Berberine (BBR), an isoquinoline-derived alkaloid isolated from Rhizoma coptidis, exerts cardioprotective effects. Because endoplasmic reticulum (ER) stress plays a pivotal role in myocardial ischemia/reperfusion (MI/R)-induced apoptosis, it was interesting to examine whether the protective effects of BBR resulted from modulating ER stress levels during MI/R injury, and to define the signaling mechanisms in this process.
Methods: Male rats were treated with BBR (200 mg · kg(-1) · d(-1), ig) for 2 weeks, and then subjected to MI/R surgery. Cardiac dimensions and function were assessed using echocardiography. Myocardial infarct size and apoptosis was examined. Total serum LDH levels and CK activities, superoxide production, MDA levels and the antioxidant SOD activities in heart tissue were determined. An in vitro study was performed on cultured rat embryonic myocardium-derived cells H9C2 exposed to simulated ischemia/reperfusion (SIR). The expression of apoptotic, ER stress-related and signaling proteins were assessed using Western blot analyses.
Results: Pretreatment with BBR significantly reduced MI/R-induced myocardial infarct size, improved cardiac function, and suppressed myocardial apoptosis and oxidative damage. Furthermore, pretreatment with BBR suppressed MI/R-induced ER stress, evidenced by down-regulating the phosphorylation levels of myocardial PERK and eIF2α and the expression of ATF4 and CHOP in heart tissues. Pretreatment with BBR also activated the JAK2/STAT3 signaling pathway in heart tissues, and co-treatment with AG490, a specific JAK2/STAT3 inhibitor, blocked not only the protective effects of BBR, but also the inhibition of BBR on MI/R-induced ER stress. In H9C2 cells, treatment with BBR (50 μmol/L) markedly reduced SIR-induced cell apoptosis, oxidative stress and ER stress, which were abolished by transfection with JAK2 siRNA.
Conclusion: BBR ameliorates MI/R injury in rats by activating the AK2/STAT3 signaling pathway and attenuating ER stress-induced apoptosis.