title: The transcription factor E26 transformation-specific sequence-1 mediates neointima formation in arteriovenous fistula.
abstract: Hemodialysis vascular access dysfunction contributes to increased morbidity and mortality in hemodialysis patients. Arteriovenous fistula (AVF) is the preferred type of vascular access for hemodialysis but has high rates of dysfunction, in part because of excessive neointima formation. The transcription factor E26 transformation-specific sequence-1 (ETS-1) is a mediator of proinflammatory responses in hypertension and endovascular injury. We examined the role of ETS-1 in the formation of neointima in AVF. Right carotid artery to internal jugular vein fistulas were created in C57BL/6 mice and assigned to treatment with an ETS-1-dominant negative peptide (ETS-DN), an inactive mutant peptide (ETS-MU), or vehicle (n=6 per group). After 7 and 21 days, AVFs or contralateral internal jugular veins were processed for PCR, immunofluorescence, immunohistochemistry, and morphometry. In AVFs, ETS-1 mRNA increased 2.5-fold at 7 days and 4-fold at 21 days. By immunofluorescence, we confirmed increased expression of ETS-1 predominantly in the neointima and overlying endothelium. Similarly, ETS-1 expression increased in human AVFs compared with normal veins. In mice, ETS-DN, but not ETS-MU, reduced neointima formation at days 7 and 21 and reduced the expression of nitric oxide synthase 2, NADPH oxidase (NOX) 2, NOX4, E-selectin, and monocyte chemotactic protein-1. Shear stress increased ETS-1 phosphorylation in human umbilical vein cells in a NOX-dependent manner, demonstrating a role for reactive oxygen species in ETS-1 activation. These results unveil the role of ETS-1 as a mediator of neointima formation in AVF and may result in the development of novel strategies for the treatment of AVF dysfunction.
authors.affiliation: Division of Nephrology.
authors.forename: Wenguang
authors.initials: W
authors.lastname: Feng
authors.forename: Phillip
authors.initials: P
authors.lastname: Chumley
authors.forename: Michael
authors.initials: M
authors.lastname: Allon
authors.forename: James
authors.initials: J
authors.lastname: George
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.forename: Rakesh P
authors.initials: RP
authors.lastname: Patel
authors.forename: Silvio
authors.initials: S
authors.lastname: Litovsky
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Jaimes
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D004195:Disease Models, Animal; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058426:Neointima / Q000209:etiology* / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000628:therapy; D013314:Stress, Mechanical
chemical_list: C494041:ETS1 protein, human; C494042:Ets1 protein, mouse; D018836:Inflammation Mediators; D050784:Proto-Oncogene Protein c-ets-1