Protective effects of Salvianolic acid B on rat ferroptosis in myocardial infarction through upregulating the Nrf2 signaling pathway

Accumulating evidence has highlighted the role of ferroptosis, a novel type of programmed cell death involved in the pathological process of myocardial infarction (MI). However, the underlying mechanism of ferroptosis in mediating MI is complicated that needs to be further investigated. Salvianolic acid B (Sal B) extracted from the traditional Chinese medicine (TCM) herb Salvia miltiorrhiza possesses pharmacological function against MI, which provides us with a new direction to explore the effect of Sal B on ferroptosis after myocardial ischemic injury. In the present study, iron accumulation and expression levels of ferroptosis-related proteins in MI rats altered in a time-dependent manner. Importantly, treatment of ferroptosis inhibitors ferrostatin-1 (Fer-1) or deferoxamine (DFO) reversed typical changes of ferroptosis, including iron overload, lipid peroxide accumulation, mitochondrial damage, and specific expression levels of ferroptosis-related proteins, thereby alleviating myocardial injury in rats. Similar results were observed in Sal B-treated MI rats in a dose-dependent manner. In addition, NFE2-related factor 2 (Nrf2) was strongly activated by the treatment of Sal B. In vivo knockdown of Nrf2 in MI rats enhanced ferroptosis and damaged the protective effect of Sal B on MI. Furthermore, Sal B administration was unable to significantly reverse expression levels of target genes of Nrf2 that were associated with iron homeostasis and oxidative stress (e.g., HO-1, xCT, Gpx4, Fth1, and Fpn1) in MI rats after knockdown of Nrf2. Taken together, Sal B contributed to protecting MI by inhibiting ferroptosis via activating the Nrf2 signaling pathway.