Dl-3-n-Butylphthalide Promotes Cardiac Function, Inhibit Oxidative Stress and Myocardial Apoptosis of Chronic Heart Failure Mice via Stimulating Nrf2/HO-1 pathway
Abstract PurposeHeart failure (HF) continues to threat the human health and plagues the world, however, there are limited effective drugs for HF. We aimed to investigate the protective effect of Dl-3-n-Butylphthalide (NBP) on myocardial injury in heart failure mice, and to study regulation mechanisms with Nrf2/HO-1/Ca2+-SERCA2a axis. MethodsSixty C57BL/6J mice were grouped into five groups using a random number table: sham group (Sham), Heart Failure model group (HF), Heart Failure+ NBP group (HN), Heart Failure+NBP+Nrf2 inhibitor (HNM), Heart Failure+ NBP + calmodulin-dependent protein kinase II (CaMKⅡ) antagonist, KN93 (HNK). The HF mice was prepared using left anterior descending coronary artery ligation. As animal model preparation, the heart function was detected using echocardiography. H&E and MASSON trichrome staining were performed to identify myocardial injury; The apoptosis of myocardial was examined by TUNEL staining assay. The levels of different oxidative stress-related proteins were measured through ELISA assay ; The reactive oxygen species and Nrf2 expression in heart tissue were observed with immunofluorescence assay. The levels of SERCA2a, calmodulin, endoplasmic reticulum stress regulatory protein and Nrf2/HO-1 protein were measured using western blotting. ResultsThe results demonstrated that NBP can significantly promote heart function, relieve the injury and inhibit cell apoptosis, meanwhile, reduce ERS injury in heart failure mice through increasing SERCA2a level and reducing Ca2+ influx. Finally, NBP was demonstrated to reduce CaMKⅡphosphorylation levels and decrease cAMP-response element binding protein phosphorylation levels, which suggested that NBP could also activate Nrf2/HO-1 signaling pathway. ConclusionsThis study identified that NPBs treatment promotes the cardiomyocytes ERS and alleviates myocardial injury in heart failure mice which is related with stimulating Nrf2/HO-1 signaling pathway, regulating Ca2+-SERCA2a and reducing Ca2+ influx.