Abstract
Myocardial ischemia/reperfusion injury is a common clinical problem and can result in severe cardiac dysfunction. Previous studies have demonstrated the protection of electroacupuncture against myocardial ischemia/reperfusion injury. However, the role of X-box binding protein I (XBP1) signaling pathway in the protection of electroacupuncture was still elusive. Thus, we designed this study and demonstrated that electroacupuncture significantly improved cardiac function during myocardial ischemia/reperfusion injury and reduced cardiac infarct size. Electroacupuncture treatment further inhibited cardiac injury manifested by the decrease of the activities of serum lactate dehydrogenase and creatine kinase-MB. The results also revealed that electroacupuncture elevated the expressions of XBP1, glucose-regulated protein 78 (GRP78), Akt, and Bcl-2 and decreased the Bax and cleaved Caspase 3 expressions. By using the inhibitor of XBP1 in vitro, the results revealed that suppression of XBP1 expression could markedly increase the activities of lactate dehydrogenase and creatine kinase-MB and cell apoptosis, thus exacerbating stimulated ischemia/reperfusion-induced H9c2 cell injury. Compared with stimulated ischemia/reperfusion group, inhibition of XBP1 inhibited the downstream GRP78 and Akt expressions during stimulated ischemia/reperfusion injury. Collectively, our data demonstrated that electroacupuncture treatment activated XBP1/GRP78/Akt signaling to protect hearts from myocardial ischemia/reperfusion injury. These findings revealed the underlying mechanisms of electroacupuncture protection against myocardial ischemia/reperfusion injury and may provide novel therapeutic targets for the clinical treatment of myocardial ischemia/reperfusion injury.
Highlights
Ischemic heart disease is a common cardiovascular problem with high morbidity and mortality [1]
myocardial ischemia/reperfusion (MI/R) significantly reduced Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) compared with sham group, while EA pretreatment for 3 consecutive days greatly increased LVEF and LVFS compared with MI/R group. These data demonstrated that MI/R resulted in compromised cardiac function, while EA pretreatment improved cardiac function, which was impaired by MI/R injury
These results indicated that the molecular mechanism of EA protection against MI/R injury was at least partly via activation of XBP1/glucose-regulated protein 78 (GRP78)/Akt signaling pathway, reducing cell apoptosis
Summary
Ischemic heart disease is a common cardiovascular problem with high morbidity and mortality [1]. As a key player of ER stress, Xbox binding protein I (XBP1) expression was induced by ATF6 and was spliced by IRE1 [5]. The resulting spliced form of XBP1 can further activate UPR to cope with ER stress [5]. In transverse aortic constriction (TAC)-induced hypertrophic and falling hearts, sustained ER stress resulted in cardiomyocyte apoptosis and contributed to the progression from cardiac hypertrophy to heart failure through the canonical and non-canonical pathways [7, 8]. Hypoxia induced ATF6 and glucose-regulated protein 78 (GRP78) expressions and protected cardiomyocytes from ischemic injury [9]. GRP78 as an XBP1 target was shown to stimulate Akt pathway to protect hearts from I/R injury [12]. The role of XBP1–Akt pathway in the MI/R injury was not fully investigated
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