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

TL;DRAbstract

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 th

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