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Mitochondrial redox plays a critical role in the paradoxical effects of NAPDH oxidase-derived ROS on coronary endothelium
Journal article   Open access   Peer reviewed

Mitochondrial redox plays a critical role in the paradoxical effects of NAPDH oxidase-derived ROS on coronary endothelium

Ehtesham Shafique, Anali Torina, Karla Reichert, Bonnie Colantuono, Nasifa Nur, Khawaja Zeeshan, Vani Ravichandran, Yuhong Liu, Jun Feng, Laura E Benjamin, …
Cardiovascular research, Vol.113(2), pp.234-246
02/2017
DOI: 10.1093/cvr/cvw249
PMCID: PMC5340144
PMID: 28088753
url
https://doi.org/10.1093/cvr/cvw249View
Published (Version of record) Open Access

Abstract

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. 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. 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.
 AMP-Activated Protein Kinases - metabolism Angiogenesis Inducing Agents - pharmacology Animals Antigens, CD - genetics Antigens, CD - metabolism Cadherins - genetics Cadherins - metabolism Cell Proliferation Cells, Cultured Coronary Vessels - drug effects Coronary Vessels - enzymology Dose-Response Relationship, Drug Endothelial Cells - drug effects Endothelial Cells - enzymology Enzyme Activation Genotype In Vitro Techniques Membrane Potential, Mitochondrial Mice, Transgenic Mitochondria - drug effects Mitochondria - enzymology NADPH Oxidases - genetics NADPH Oxidases - metabolism Neovascularization, Physiologic Nitric Oxide - metabolism Nitric Oxide Synthase Type III - metabolism Oxidation-Reduction Phenotype Phosphorylation Reactive Oxygen Species - metabolism Signal Transduction Superoxide Dismutase - metabolism Time Factors Tyrosine - analogs & derivatives Tyrosine - metabolism Vasodilation Vasodilator Agents - pharmacology

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