Oxidant‐induced Endothelial Dysfunction is a failure of the Mitochondria to Process Cytosolic ROS

Abstract

Introduction Increased ROS is associated with vascular pathology. Recent reports showed that whereas short-term (4 weeks) increase in NADPH oxidase-derived endothelium (EC)-specific ROS improved coronary endothelial function, long-term (16+ weeks) increase in ROS had adverse effects. Hypothesis We tested the hypothesis that short-term (4-8 weeks) ROS increase induces AMPK-FOXO1-mediated expression of SOD2 and thus exert protective effects on EC mitochondria; in contrast, long-term (16-20 weeks) ROS increase results in nitrotyration and inactivation of MnSOD, mitochondrial membrane potential loss, and mitophagy in EC. Results: Our binary (Tet-ON/OFF) conditional transgenic mouse (Tet-Nox2:VE-Cad-tTA) induces 1.8±0.42-fold increase in ROS in endothelium. Using these animals, we have examined the effects of short-term vs. the long-term effects of ROS on EC signaling, mitochondrial activity, and coronary endothelial function (microvessel reactivity). Isolated ECs from mouse heart showed that both short-term and long-term increase in ROS induced AMPK and eNOS, and nitric oxide (NO) synthesis, however, long-term increase in ROS abrogated these positive effects due to increased peroxynitrite levels and nitrotyration of MnSOD. Long-term ROS increase also results in mitochondrial membrane potential loss, reduction in mitochondrial content and EC function. Conclusion We report that whereas short-term increase in ROS is beneficial for EC function, long-term increase results in mitochondrial damage and inhibition of endothelial function.