Costunolide (Cos) is a naturally occurring sesquiterpene lactone that exhibits antioxidative properties. In this study, we demonstrate the protective mechanism of Cos against ischemia/reperfusion (I/R)-induced myocardial injury. Cos significantly decreased levels of reactive oxygen species and ameliorated apoptosis of I/R cardiomyocytes both in vitro and in vivo. Further investigation revealed that Cos increased expression of the antioxidant proteins HO-1 and NQO-1 and decreased the Bax/Bcl-2 ratio, thus protecting cardiac cells. NF-E2-related factor 2 (Nrf2) silencing significantly attenuated the protective effects of Cos in tert-butyl hydroperoxide (TBHP)-treated H9C2 cells. Additionally, Cos significantly intensified the I/R- or TBHP-induced dissociation of the Kelch-like ECH-associated protein 1 (Keap1)/Nrf2 complex both in vitro and in vivo. These results suggest that activation of Nrf2/Keap1 using Cos may be a therapeutic strategy for myocardial I/R injury.
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