Abstract 17242: Role Reversal of Oxidants in Coronary Endothelium: Short-term vs Long-term Exposure
Introduction: Increase in reactive oxygen species (ROS) is often associated with vascular pathophysiological conditions. Our recent findings demonstrated that whereas short-term (4 weeks) increase in NADPH oxidase-derived endothelium (EC)-specific ROS improved coronary endothelial function, long-term (16 plus weeks) increase in ROS had adverse effects.
Hypothesis: We tested the hypothesis that short-term (four to eight weeks) increase in EC-ROS induces AMPK-FOXO1-mediated expression of SOD2 and thus exert protective effects on EC mitochondria; whereas long-term (16 to 20 weeks) increase in EC-ROS results in nitrotyration and inactivation of MnSOD leading to mitochondrial membrane potential loss and mitophagy leading to oxidative damage to EC.
Methods: Our binary (Tet-ON/OFF) conditional transgenic mouse (Tet-Nox2:VE-Cad-tTA) induces 1.8±0.42-fold increase in NADPH oxidase-derived 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, EC proliferation, and coronary endothelial function (microvessel reactivity).
Results: We demonstrate that whereas EC-dependent coronary vasodilation was significantly increased after short-term increase in ROS, coronary vasodilation was drastically reduced after long-term increase in EC-ROS in Tet-OFF Nox2 mice compared to the control littermates. Using EC isolated from mouse heart, we demonstrate that, whereas Nox2-derived both short-term and long-term increase in ROS increased activation of AMPK and eNOS, and nitric oxide (NO) synthesis, long-term increase in ROS abrogated these positive effects due to increased peroxynitrite levels and nitrotyration of MnSOD. We also show that long-term ROS increase results in mitochondrial membrane potential loss, reduction in mitochondrial content and EC proliferation.
Conclusion: This study demonstrates that whereas short-term increase in ROS is beneficial for EC function, long-term increase in ROS results in EC mitochondrial damage, reduction in EC proliferation, and inhibition of endothelial function. Ongoing LAD ligation studies are being carried out in the lab to examine the effects of endothelial ROS on myocardial preservation.
Author Disclosures: R. Abid: None. E. Shafique: None. Y. Liu: None. J. Feng: None. L.E. Benjamin: None. E. Harrington: None. F.W. Sellke: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.