Tanshinone IIA inhibits Leu27IGF‐II‐induced insulin‐like growth factor receptor II signaling and myocardial apoptosis via estrogen receptor‐mediated Akt activation

Abstract Different stress condition stimulates the expression level of insulin‐like growth factor receptor II (IGF‐IIR) in cardiomyoblasts that lead to apoptosis. Tanshinone IIA (TSN), a pharmacologically active component from Danshen, has been shown cardioprotective effects against cardiac apoptosis induced by several stress conditions. Therefore, this study was conducted to assess the cardioprotective effects of TSN IIA mediated through the estrogen receptor (ER) in order to inhibit the Leu27IGF‐II‐enhanced IGF‐IIR‐mediated cardiac apoptosis. The estrogenic activity of TSN IIA was examined after myocardial cells were pretreated with the ER antagonist, and inhibited the phospho‐inositide‐3 kinase (PI3K). Here, we found that TSN IIA significantly induced ER that phosphorylated Akt. Further, Akt activation considerably suppressed the Leu27IGF‐II induced IGF‐IIR expression level and the downstream effectors, including Gαq and calcineurin as well as mitochondrial dependent apoptosis proteins including Bad, cytochrome c , and active caspase‐3 that result in cardiac apoptosis resistance. However, the western blot analysis, JC‐1 staining, and terminal deoxynucleotide transferase‐mediated dUTP nick end labeling assay revealed that TSN IIA attenuated Leu27IGF‐II‐induced IGF‐IIR mediated cardiac apoptosis was reversed by an ER antagonist such as ICI 182780, and PI3K inhibition. All these findings demonstrate that TSN IIA exerts estrogenic activity, which can activate PI3K‐Akt pathway, and thereby inhibits Leu27IGFII induced IGF‐IIR mediated cardiac apoptosis. Thus, TSN IIA can be considered as an effective therapeutic strategy against IGF‐IIR signaling cascade to suppress cardiac apoptosis.