Inhibition of Endothelin‐1‐induced IGF‐1R, PKB and ERK1/2 phosphorylation, as well as hypertrophic and proliferative responses, by Curcumin in Vascular Smooth Muscle Cells

Endothelin‐1 (ET‐1) has been implicated in the pathogenesis of vascular abnormalities, such as hypertension and atherosclerosis, through the hyperactivation of growth promoting pathways, including MAPKs and PI3K/PKB. ET‐1 has been shown to elicit its responses through the generation of reactive oxygen species (ROS). We have demonstrated earlier that insulin‐like growth factor‐1 receptor (IGF‐1R) plays a role in transducing the effect of H2O2, leading to PKB phosphorylation. Curcumin, the main constituent of the spice turmeric, has been shown to exhibit cardio‐protective, anti‐proliferative and anti‐oxidant properties; however, the precise molecular mechanism of its action is not fully understood. Therefore, in the present studies, we investigated the effects of curcumin on ET‐1‐induced IGF‐1R, PKB and ERK1/2 phosphorylation, as well as its anti‐proliferative and anti‐oxidant responses in VSMC. Treatment of VSMC with ET‐1 induced the phosphorylation of IGF‐1R, PKB and ERK1/2, which was inhibited in a dose‐dependant fashion by curcumin. Furthermore, protein and DNA synthesis enhanced by ET‐1 were also attenuated by curcumin, as was ET‐1‐induced ROS generation in VSMC. In summary, these data suggest that curcumin may exert its anti‐proliferative and anti‐oxidant effects through an inhibition of ET‐1‐induced growth promoting signaling events. (Supported by grants from CIHR)