The Role of FoxO1 and Sex Differences in Response to a DNA-damaging Agent

Endothelial cell (EC) health can be disturbed in various diseases like aging, obesity, atherosclerosis and type 2 diabetes. Previously, our lab showed that female ECs retain a healthier phenotype than male ECs under obesogenic conditions and that they have higher levels of Forkhead Box O1 (FoxO1) than male ECs. The goal was to investigate whether FoxO1 inhibition enhances EC vulnerability and whether any sex differences occur in response to an oxidant insult. To achieve this, ECs were treated with a FoxO1 inhibitor and treated with cisplatin. FoxO1 inhibition promoted cell cycle arrest and antioxidant induction in both sexes while DNA damage improved only in male ECs. Unperturbed female ECs displayed higher levels of γH2AX compared to male ECs. These data provide evidence that FoxO1 inhibition is potentially protective for the male EC while also revealing a potential sex disparity in the DNA damage response pathway.