Expression of CD70 modulates nitric oxide and redox status in endothelial cells

Pandey, Arvind K. and Waldeck-Weiermair, Markus and Wells, Quinn S. and Xiao, Wusheng and Yadav, Shambhu and Eroğlu, Emrah and Michel, Thomas and Loscalzo, Joseph (2022) Expression of CD70 modulates nitric oxide and redox status in endothelial cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 42 (9). pp. 1169-1185. ISSN 1079-5642 (Print) 1524-4636 (Online)

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Background: Endothelial dysfunction is a critical component in the pathogenesis of cardiovascular diseases and is closely associated with nitric oxide (NO) levels and oxidative stress. Here, we report on novel findings linking endothelial expression of CD70 (also known as CD27 ligand) with alterations in NO and reactive oxygen species. Methods: CD70 expression was genetically manipulated in human aortic and pulmonary artery endothelial cells. Intracellular NO and hydrogen peroxide (H2O2) were measured using genetically encoded biosensors, and cellular phenotypes were assessed. Results: An unbiased phenome-wide association study demonstrated that polymorphisms in CD70 associate with vascular phenotypes. Endothelial cells treated with CD70-directed short-interfering RNA demonstrated impaired wound closure, decreased agonist-stimulated NO levels, and reduced eNOS (endothelial nitric oxide synthase) protein. These changes were accompanied by reduced NO bioactivity, increased 3-nitrotyrosine levels, and a decrease in the eNOS binding partner heat shock protein 90. Following treatment with the thioredoxin inhibitor auranofin or with agonist histamine, intracellular H2O2levels increased up to 80% in the cytosol, plasmalemmal caveolae, and mitochondria. There was increased expression of NADPH oxidase 1 complex and gp91phox; expression of copper/zinc and manganese superoxide dismutases was also elevated. CD70 knockdown reduced levels of the H2O2scavenger catalase; by contrast, glutathione peroxidase 1 expression and activity were increased. CD70 overexpression enhanced endothelial wound closure, increased NO levels, and attenuated the reduction in eNOS mRNA induced by TNFα. Conclusions: Taken together, these data establish CD70 as a novel regulatory protein in endothelial NO and reactive oxygen species homeostasis, with implications for human vascular disease.
Item Type: Article
Uncontrolled Keywords: CD27 ligand; endothelial dysfunction; homeostasis; nitric oxide synthase type III; reactive oxygen species
Divisions: Faculty of Engineering and Natural Sciences
Depositing User: Emrah Eroğlu
Date Deposited: 21 Sep 2022 11:34
Last Modified: 21 Sep 2022 11:34

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