FOXO1 Couples Reactive Oxygen Species in Diabetic Atherosclerosis

Abstract

Diabetic atherosclerosis, distinct from other type of atherosclerosis, is progressing rapidly which is the leading cause of morbidity and mortality in the entire world, and no effective therapy has been established so far. Thus, an intensive search for new therapeutic targets in diabetic atherosclerosis is needed. A growing evidences are that post translational modifications of FOXO1 triggered by hyperglycemia-induced reactive oxygen species (ROS) which is most likely primarily responsible for hyperglycemia, plays an important role in diabetic atherosclerosis progression.Here, we investigated whether the inhibition of FOXO1 alters diabetes-associated atherosclerosis. Our study found that pharmacologic inhibition of FOXO1 markedly suppressed the vascular remodeling in DM though attenuating overproduction of ROS, increasing antioxidant function in conjunction with enhancing antioxidant activity, and reducing ROS induced inflammation and fibrosis in carotid artery. Moreover, in T1DM rats, FOXO1 translocate into the tunica intima of carotid artery after treatment of pharmacologic inhibition of FOXO1, which coupled with the activation of PI3K/Akt/mTOR pathway. In addition, inactivation of PI3K/Akt/mTOR pathway in diabetic carotid artery was restored by pharmacologic inhibition of FOXO1 and the anti-ROS effect of pharmacologic inhibition of FOXO1 was partially inhibited by a PI3K inhibitor (LY294002) and also enhanced p-Akt/Akt protein ratio. Therefore, we hypothesis that pharmacologic inhibition of FOXO1 attenuate hyperglycemia-induced ROS generation associated with activation of PI3K/Akt/mTOR pathway signaling, which may be a promising target for treating diabetic atherosclerosis and subsequent cardiovascular diseases.