Endothelial Cell Nrf2 Activation Inhibits Atherosclerosis

Atherosclerosis, a chronic inflammatory disease closely associated with obesity, diabetes, high blood pressure and unfavorable lifestyle, is initiated by abnormal lipid deposition in vascular lumen to form “fatty streak” which is resulted from damaged endothelial function and integrity by oxidative stress and inflammation. Lipid-lowering drugs such as statins commonly used to treat atherosclerotic vascular diseases possess anti-oxidant or/and anti-inflammatory properties.Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcriptional factor plays critical roles in controlling oxidative stress/inflammation. When activated by reactive oxygen species (ROS) or cellular electrophiles, Nrf2 restores redox balance and limits inflammation by regulating expressions of >250 genes through binding to the antioxidant response element in their promoter regions. The Nrf2-targeted genes are composed of genes related to redox balance, anti-inflammation and pentoses metabolism, thus limiting inflammation and minimizing ROS-induced cellular damage.Previous studies on the role of Nrf2 in atherosclerosis was confined mainly to macrophages. Global Nrf2 knockout and bone marrow transplantation are commonly used transgenic mouse models. Due to lack of tissue specificity, conflicting results were reported. The in vitro experiments showed that athero-protective laminar shear stress increases the expression and nuclear translocation of Nrf2, rendering protection of endothelial function. Nrf2 overexpression inhibits vascular smooth muscle cell proliferation, indicating an anti-atherogenic potential of Nrf2 activation. However, the exact role of endothelial Nrf2 in atherogenesis is unknown.Our preliminary results show that expressions of Nrf2 target genes were increased in aortic endothelial cells of atherosclerotic ApoE-/- mice at both early and later stages of atherosclerosis. Nrf2 knockdown aggravated TNF-α-induced inflammatory response in human umbilical vein endothelial cells (HUVECs). In addition, dimethyl itaconate (DMI), an activator of Nrf2, suppressed expressions of inflammatory genes induced by TNF-α and disturbed flow in HUVECs. In vivo experiments also show that DMI inhibited plaques formation in ApoE-/- mice. These promising observations prompted us to hypothesize that activation of endothelial Nrf2 is athero-protective and targeting this signaling pathway could serve as another potentially effective strategy in the prevention and treatment of atherosclerosis.This proposed study shall be the first of its type to investigate the role of endothelial Nrf2 in atherogenesis. Since Nrf2 is involved in the regulation of ROS, inflammation, and metabolism, this study shall deepen our understanding of interactions between these three important determinants in atherogenesis. The results of this study shall provide new target(s) for prevention and treatment of atherosclerosis and hopefully for development of new drugs against atherosclerosis.