Journal
CARDIOVASCULAR RESEARCH
Volume 113, Issue 2, Pages 234-246Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvw249
Keywords
Endothelium; Signal transduction; Nitric oxide; Reactive oxygen species; NADPH oxidase
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Funding
- Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health [P20 GM103652]
- American Heart Association (AHA) [14GRNT20460291]
- Brazilian government grants [2011/14550-7, 2012/09130-1]
- National Heart, Lung, and Blood Institute (NHLBI) [HL46716, R25 HL088992]
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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 (Delta psi m), 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 Delta psi m followed by inhibition of endothelial function and proliferation.
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