Impact of eNOS-Dependent Oxidative Stress on Endothelial Function and Neointima Formation

Antioxidants & Redox Signaling
Tatsiana SuvoravaGeorg Kojda

Abstract

Vascular oxidative stress generated by endothelial NO synthase (eNOS) was observed in experimental and clinical cardiovascular disease, but its relative importance for vascular pathologies is unclear. We investigated the impact of eNOS-dependent vascular oxidative stress on endothelial function and on neointimal hyperplasia. A dimer-destabilized mutant of bovine eNOS where cysteine 101 was replaced by alanine was cloned and introduced into an eNOS-deficient mouse strain (eNOS-KO) in an endothelial-specific manner. Destabilization of mutant eNOS in cells and eNOS-KO was confirmed by the reduced dimer/monomer ratio. Purified mutant eNOS and transfected cells generated less citrulline and NO, respectively, while superoxide generation was enhanced. In eNOS-KO, introduction of mutant eNOS caused a 2.3-3.7-fold increase in superoxide and peroxynitrite formation in the aorta and myocardium. This was completely blunted by an NOS inhibitor. Nevertheless, expression of mutant eNOS in eNOS-KO completely restored maximal aortic endothelium-dependent relaxation to acetylcholine. Neointimal hyperplasia induced by carotid binding was much larger in eNOS-KO than in mutant eNOS-KO and C57BL/6, while the latter strains showed comparable hyperpla...Continue Reading

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Citations

Nov 21, 2015·Life Sciences·Alessandra BielliAugusto Orlandi
Jun 15, 2015·Bioorganic & Medicinal Chemistry·Gerda Brunhofer-BolzerThomas Erker
Jan 10, 2019·International Journal of Molecular Sciences·Andreas DaiberHuige Li
Jun 2, 2018·Oxidative Medicine and Cellular Longevity·Ralf ErkensMiriam M Cortese-Krott

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Methods Mentioned

BETA
transfection
fluorescence microscopy
transgenic
pharmacotherapy
electrophoresis

Software Mentioned

GraphPad Prism
Leica

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