Insulin-like growth factor-1 receptor activation prevents hydrogen peroxide-induced oxidative stress, mitochondrial dysfunction and apoptosis.

Vascular disease is the leading cause of morbidity and mortality. Oxidative stress can cause endothelial cell apoptosis. Low insulin like growth factor-1 (IGF-1) has been linked to adverse risk profile and increased vascular disease incidence. Since IGF-1 acts as an important survival factor for multiple cell types, we undertook this study to investigate whether IGF-1 favorably affects oxidative-stress mediated apoptosis of vascular endothelial cells. Exposure to hydrogen peroxide induced apoptotic changes (e.g. DNA fragmentation, altered mitochondrial membrane potential and caspase-3 activity) in human umbilical vein endothelial cells (HUVECs) in a time dependent manner. Addition of IGF-1 blocked the oxidative-stress effect parallel to IGF-1 receptor (IGF-1R) expression, and silencing the IGF-1R with small interference RNA attenuated the IGF-1 influence. Our findings show that enhanced IGF-1 signaling inhibits oxidative-stress induced apoptosis in HUVECs by reducing mitochondrial dysfunction. Specifically the protective mechanism of IGF-1 involves preserving the mitochondrial membrane potential, maintaining the mitochondrial retention of cytochrome-c, and reducing caspase-3 activity. These results may have therapeutic implications in preventing/reducing vascular disease associated endothelial dysfunction.