Expression of CD70 Modulates Nitric Oxide and Redox Status in Endothelial Cells. Issue 9 (4th August 2022)

• Record Type: Journal Article
• Authors: Pandey, Arvind K.; Waldeck-Weiermair, Markus; Wells, Quinn S.; Xiao, Wusheng; Yadav, Shambhu; Eroglu, Emrah; Michel, Thomas; Loscalzo, Joseph
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 42:Issue 9(2022)
• Page Start: 1169
• Page End: 1185
• Publication Date: 2022-08-04
• Subjects: CD27 ligand -- endothelial dysfunction -- homeostasis -- nitric oxide synthase type III -- reactive oxygen species; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.122.317866
• Languages: English
• ISSNs: 1079-5642

Abstract

Abstract : 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 (H2 O2 ) 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 H2 O2 levels 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 H2 O2 scavenger 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.