Protective effect of Fisetin against angiotensin II-induced apoptosis by activation of IGF-IR-PI3K-Akt signaling in H9c2 cells and spontaneous hypertension rats

Fisetin, a polyphenolic compound, has drawn notable attention owing to its antioxidant, anti-inflammatory, anti-cancer and neuroprotective effects. However, the cardiac effects of fisetin are not clear yet.The aim of the present study is to examine the cardioprotective effect of fisetin against Ang-II induced apoptosis in H9c2 cells and in spontaneous hypertensive rats (SHR).The in vitro protective effect of fisetin was evaluated after the cells were treated with fisetin (50 µM/ml/ 24 h) for 2 h prior or after Ang-II administration to induce apoptosis. For in vivo experiments, SHRs were orally administered with fisetin (10 mg/kg) twice a week for 6 weeks. Cellular apoptosis was analyzed by TUNEL staining assay and the modulation in the expression levels of proteins involved in apoptosis and cell survival were determined by western blotting.Our results demonstrate the potent cardioprotective efficacy of fisetin against Ang-II induced apoptosis in H9c2 cells and in SHR models. Fisetin administration reduced the apoptotic nuclei considerably And reduced the expression of apoptotic proteins such as TNF- α, Fas L, FADD, Cleaved caspase-3 and Cleaved PARP and increased the cell survival and anti-apoptotic proteins like Bcl-2, Bcl-xL, p-IGF1R, p-PI3K and p-AKT in both in vitro and in vivo models.In conclusion, the results of the present study reveal that fisetin activates the IGF-IR-dependent p-PI3K/p-Akt survival signaling pathway and suppresses the caspase dependent apoptosis.