Ehtesham Shafique1, Anali Torina1, Karla Reichert1, Bonnie Colantuono1, Nasifa Nur1, Khawaja Zeeshan1, Vani Ravichandran1, Yuhong Liu1,2, Jun Feng1,2, Khawaja Zeeshan1, Laura E Benjamin3, Kaikobad Irani4, Elizabeth O Harrington5,6, Frank W Sellke1,2, Md Ruhul Abid7,2,6. 1. Cardiovascular Research Center, Division of Cardiothoracic Surgery, Department of Surgery, Rhode Island Hospital, 1 Hoppin St, Providence, RI 02903, USA. 2. Warren Alpert Medical School of Brown University, 593 Eddy St, Providence, RI 02903, USA. 3. Imclone, 180 Varick St, New York, NY 10014, USA. 4. University of Iowa Carver School of Medicine, Iowa, IA, USA. 5. Providence VA Medical Center, Providence, RI, USA. 6. Brown University, Providence, RI, USA. 7. Cardiovascular Research Center, Division of Cardiothoracic Surgery, Department of Surgery, Rhode Island Hospital, 1 Hoppin St, Providence, RI 02903, USA; ruhul_abid@brown.edu.
Abstract
AIMS: There are conflicting reports on the role of reactive oxygen species (ROS) i.e. beneficial vs. harmful, in vascular endothelium. Here, we aim to examine whether duration of exposure to ROS and/or subcellular ROS levels are responsible for the apparently paradoxical effects of oxidants on endothelium. METHODS AND RESULTS: We have recently generated binary (Tet-ON/OFF) conditional transgenic mice (Tet-Nox2:VE-Cad-tTA) that can induce 1.8 ± 0.42-fold increase in NADPH oxidase (NOX)-derived ROS specifically in vascular endothelium upon withdrawal of tetracycline from the drinking water. Animals were divided in two groups: one exposed to high endogenous ROS levels for 8 weeks (short-term) and the other for 20 weeks (long-term). Using endothelial cells (EC) isolated from mouse hearts (MHEC), we demonstrate that both short-term and long-term increase in NOX-ROS induced AMPK-mediated activation of eNOS. Interestingly, although endothelium-dependent nitric oxide (NO)-mediated coronary vasodilation was significantly increased after short-term increase in NOX-ROS, coronary vasodilation was drastically reduced after long-term increase in ROS. We also show that short-term ROS increase induced proliferation in EC and angiogenic sprouting in the aorta. In contrast, long-term increase in cytosolic ROS resulted in nitrotyrosine-mediated inactivation of mitochondrial (mito) antioxidant MnSOD, increase in mito-ROS, loss of mitochondrial membrane potential (Δψm), decreased EC proliferation and angiogenesis. CONCLUSION: The findings suggest that NOX-derived ROS results in increased mito-ROS. Whereas short-term increase in mito-ROS was counteracted by MnSOD, long-term increase in ROS resulted in nitrotyrosine-mediated inactivation of MnSOD, leading to unchecked increase in mito-ROS and loss of Δψm followed by inhibition of endothelial function and proliferation. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: There are conflicting reports on the role of reactive oxygen species (ROS) i.e. beneficial vs. harmful, in vascular endothelium. Here, we aim to examine whether duration of exposure to ROS and/or subcellular ROS levels are responsible for the apparently paradoxical effects of oxidants on endothelium. METHODS AND RESULTS: We have recently generated binary (Tet-ON/OFF) conditional transgenic mice (Tet-Nox2:VE-Cad-tTA) that can induce 1.8 ± 0.42-fold increase in NADPH oxidase (NOX)-derived ROS specifically in vascular endothelium upon withdrawal of tetracycline from the drinking water. Animals were divided in two groups: one exposed to high endogenous ROS levels for 8 weeks (short-term) and the other for 20 weeks (long-term). Using endothelial cells (EC) isolated from mouse hearts (MHEC), we demonstrate that both short-term and long-term increase in NOX-ROS induced AMPK-mediated activation of eNOS. Interestingly, although endothelium-dependent nitric oxide (NO)-mediated coronary vasodilation was significantly increased after short-term increase in NOX-ROS, coronary vasodilation was drastically reduced after long-term increase in ROS. We also show that short-term ROS increase induced proliferation in EC and angiogenic sprouting in the aorta. In contrast, long-term increase in cytosolic ROS resulted in nitrotyrosine-mediated inactivation of mitochondrial (mito) antioxidant MnSOD, increase in mito-ROS, loss of mitochondrial membrane potential (Δψm), decreased EC proliferation and angiogenesis. CONCLUSION: The findings suggest that NOX-derived ROS results in increased mito-ROS. Whereas short-term increase in mito-ROS was counteracted by MnSOD, long-term increase in ROS resulted in nitrotyrosine-mediated inactivation of MnSOD, leading to unchecked increase in mito-ROS and loss of Δψm followed by inhibition of endothelial function and proliferation. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Anna E Dikalova; Alfiya T Bikineyeva; Klaudia Budzyn; Rafal R Nazarewicz; Louise McCann; William Lewis; David G Harrison; Sergey I Dikalov Journal: Circ Res Date: 2010-05-06 Impact factor: 17.367
Authors: Masuko Ushio-Fukai; Yan Tang; Tohru Fukai; Sergey I Dikalov; Yuxian Ma; Mitsuaki Fujimoto; Mark T Quinn; Patrick J Pagano; Chad Johnson; R Wayne Alexander Journal: Circ Res Date: 2002-12-13 Impact factor: 17.367
Authors: Andrew C Little; Arvis Sulovari; Karamatullah Danyal; David E Heppner; David J Seward; Albert van der Vliet Journal: Free Radic Biol Med Date: 2017-05-31 Impact factor: 7.376