Increased production of superoxide anion contributes to dysfunction of the arteriovenous fistula

Mykola V. Tsapenko, Livius V. d'Uscio, Joseph Peter Grande, Anthony J. Croatt, Melissa C. Hernandez, Allan W. Ackerman, Zvonimir S Katusic, Karl A Nath

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Vascular access dysfunction causes morbidity in hemodialysis patients. This study examined the generation and pathobiological significance of superoxide anion in a rat femoral arteriovenous fistula (AVF). One week after AVF creation, there was increased production of superoxide anion accompanied by decreased total superoxide dismutase (SOD) and Cu/Zn SOD activities and induction of the redox-sensitive gene heme oxygenase-1. Immunohistochemical studies of nitrotyrosine formation demonstrated that peroxynitrite, a product of superoxide anion and nitric oxide, was present in increased amounts in endothelial and smooth muscle cells in the AVF. Because uncoupled NOS isoforms generate superoxide anion, and NOS coupling requires tetrahydrobiopterin (BH4) as a cofactor, we assessed NOS uncoupling by determining the ratio of BH4 to dihydrobiopterin (BH2); the BH4-to-BH2 ratio was markedly attenuated in the AVF. Because Src is a vasculopathic signaling species upstream and downstream of superoxide anion, such expression was evaluated; expression of Src and phosphorylated Src was both markedly increased in the AVF. Expression of NADPH oxidase (NOX) 1, NOX2, NOX4, cyclooxygenase (COX) 1, COX2, p47phox, and p67phox was all unchanged, as assessed by Western analyses, thereby suggesting that these proteins may not be involved in increased production of superoxide anion. Finally, administration of tempol, a superoxide anion scavenger, decreased neointima formation in the juxta-anastomotic venous segment and improved AVF blood flow. We conclude that the AVF exhibits increased superoxide anion generation that may reflect the combined effects of decreased scavenging by SOD and increased generation by uncoupled NOS, and that enhanced superoxide anion production promotes juxta-anastomotic stenosis and impairs AVF function.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume303
Issue number12
DOIs
StatePublished - Dec 15 2012

Fingerprint

Arteriovenous Fistula
Superoxides
Superoxide Dismutase
Neointima
Cyclooxygenase 1
Heme Oxygenase-1
Peroxynitrous Acid
Thigh
Oxidation-Reduction
Smooth Muscle Myocytes
Blood Vessels
Renal Dialysis
Nitric Oxide
Pathologic Constriction
Protein Isoforms
Morbidity

Keywords

  • Hemodialysis
  • Nitric oxide synthase
  • Oxidant stress
  • Tetrahydrobiopterin
  • Vascular access dysfunction

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Increased production of superoxide anion contributes to dysfunction of the arteriovenous fistula. / Tsapenko, Mykola V.; d'Uscio, Livius V.; Grande, Joseph Peter; Croatt, Anthony J.; Hernandez, Melissa C.; Ackerman, Allan W.; Katusic, Zvonimir S; Nath, Karl A.

In: American Journal of Physiology - Renal Physiology, Vol. 303, No. 12, 15.12.2012.

Research output: Contribution to journalArticle

Tsapenko, Mykola V. ; d'Uscio, Livius V. ; Grande, Joseph Peter ; Croatt, Anthony J. ; Hernandez, Melissa C. ; Ackerman, Allan W. ; Katusic, Zvonimir S ; Nath, Karl A. / Increased production of superoxide anion contributes to dysfunction of the arteriovenous fistula. In: American Journal of Physiology - Renal Physiology. 2012 ; Vol. 303, No. 12.
@article{5dcfc073f5ff4182855c243425a27cef,
title = "Increased production of superoxide anion contributes to dysfunction of the arteriovenous fistula",
abstract = "Vascular access dysfunction causes morbidity in hemodialysis patients. This study examined the generation and pathobiological significance of superoxide anion in a rat femoral arteriovenous fistula (AVF). One week after AVF creation, there was increased production of superoxide anion accompanied by decreased total superoxide dismutase (SOD) and Cu/Zn SOD activities and induction of the redox-sensitive gene heme oxygenase-1. Immunohistochemical studies of nitrotyrosine formation demonstrated that peroxynitrite, a product of superoxide anion and nitric oxide, was present in increased amounts in endothelial and smooth muscle cells in the AVF. Because uncoupled NOS isoforms generate superoxide anion, and NOS coupling requires tetrahydrobiopterin (BH4) as a cofactor, we assessed NOS uncoupling by determining the ratio of BH4 to dihydrobiopterin (BH2); the BH4-to-BH2 ratio was markedly attenuated in the AVF. Because Src is a vasculopathic signaling species upstream and downstream of superoxide anion, such expression was evaluated; expression of Src and phosphorylated Src was both markedly increased in the AVF. Expression of NADPH oxidase (NOX) 1, NOX2, NOX4, cyclooxygenase (COX) 1, COX2, p47phox, and p67phox was all unchanged, as assessed by Western analyses, thereby suggesting that these proteins may not be involved in increased production of superoxide anion. Finally, administration of tempol, a superoxide anion scavenger, decreased neointima formation in the juxta-anastomotic venous segment and improved AVF blood flow. We conclude that the AVF exhibits increased superoxide anion generation that may reflect the combined effects of decreased scavenging by SOD and increased generation by uncoupled NOS, and that enhanced superoxide anion production promotes juxta-anastomotic stenosis and impairs AVF function.",
keywords = "Hemodialysis, Nitric oxide synthase, Oxidant stress, Tetrahydrobiopterin, Vascular access dysfunction",
author = "Tsapenko, {Mykola V.} and d'Uscio, {Livius V.} and Grande, {Joseph Peter} and Croatt, {Anthony J.} and Hernandez, {Melissa C.} and Ackerman, {Allan W.} and Katusic, {Zvonimir S} and Nath, {Karl A}",
year = "2012",
month = "12",
day = "15",
doi = "10.1152/ajprenal.00449.2012",
language = "English (US)",
volume = "303",
journal = "American Journal of Physiology - Renal Fluid and Electrolyte Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "12",

}

TY - JOUR

T1 - Increased production of superoxide anion contributes to dysfunction of the arteriovenous fistula

AU - Tsapenko, Mykola V.

AU - d'Uscio, Livius V.

AU - Grande, Joseph Peter

AU - Croatt, Anthony J.

AU - Hernandez, Melissa C.

AU - Ackerman, Allan W.

AU - Katusic, Zvonimir S

AU - Nath, Karl A

PY - 2012/12/15

Y1 - 2012/12/15

N2 - Vascular access dysfunction causes morbidity in hemodialysis patients. This study examined the generation and pathobiological significance of superoxide anion in a rat femoral arteriovenous fistula (AVF). One week after AVF creation, there was increased production of superoxide anion accompanied by decreased total superoxide dismutase (SOD) and Cu/Zn SOD activities and induction of the redox-sensitive gene heme oxygenase-1. Immunohistochemical studies of nitrotyrosine formation demonstrated that peroxynitrite, a product of superoxide anion and nitric oxide, was present in increased amounts in endothelial and smooth muscle cells in the AVF. Because uncoupled NOS isoforms generate superoxide anion, and NOS coupling requires tetrahydrobiopterin (BH4) as a cofactor, we assessed NOS uncoupling by determining the ratio of BH4 to dihydrobiopterin (BH2); the BH4-to-BH2 ratio was markedly attenuated in the AVF. Because Src is a vasculopathic signaling species upstream and downstream of superoxide anion, such expression was evaluated; expression of Src and phosphorylated Src was both markedly increased in the AVF. Expression of NADPH oxidase (NOX) 1, NOX2, NOX4, cyclooxygenase (COX) 1, COX2, p47phox, and p67phox was all unchanged, as assessed by Western analyses, thereby suggesting that these proteins may not be involved in increased production of superoxide anion. Finally, administration of tempol, a superoxide anion scavenger, decreased neointima formation in the juxta-anastomotic venous segment and improved AVF blood flow. We conclude that the AVF exhibits increased superoxide anion generation that may reflect the combined effects of decreased scavenging by SOD and increased generation by uncoupled NOS, and that enhanced superoxide anion production promotes juxta-anastomotic stenosis and impairs AVF function.

AB - Vascular access dysfunction causes morbidity in hemodialysis patients. This study examined the generation and pathobiological significance of superoxide anion in a rat femoral arteriovenous fistula (AVF). One week after AVF creation, there was increased production of superoxide anion accompanied by decreased total superoxide dismutase (SOD) and Cu/Zn SOD activities and induction of the redox-sensitive gene heme oxygenase-1. Immunohistochemical studies of nitrotyrosine formation demonstrated that peroxynitrite, a product of superoxide anion and nitric oxide, was present in increased amounts in endothelial and smooth muscle cells in the AVF. Because uncoupled NOS isoforms generate superoxide anion, and NOS coupling requires tetrahydrobiopterin (BH4) as a cofactor, we assessed NOS uncoupling by determining the ratio of BH4 to dihydrobiopterin (BH2); the BH4-to-BH2 ratio was markedly attenuated in the AVF. Because Src is a vasculopathic signaling species upstream and downstream of superoxide anion, such expression was evaluated; expression of Src and phosphorylated Src was both markedly increased in the AVF. Expression of NADPH oxidase (NOX) 1, NOX2, NOX4, cyclooxygenase (COX) 1, COX2, p47phox, and p67phox was all unchanged, as assessed by Western analyses, thereby suggesting that these proteins may not be involved in increased production of superoxide anion. Finally, administration of tempol, a superoxide anion scavenger, decreased neointima formation in the juxta-anastomotic venous segment and improved AVF blood flow. We conclude that the AVF exhibits increased superoxide anion generation that may reflect the combined effects of decreased scavenging by SOD and increased generation by uncoupled NOS, and that enhanced superoxide anion production promotes juxta-anastomotic stenosis and impairs AVF function.

KW - Hemodialysis

KW - Nitric oxide synthase

KW - Oxidant stress

KW - Tetrahydrobiopterin

KW - Vascular access dysfunction

UR - http://www.scopus.com/inward/record.url?scp=84871295157&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84871295157&partnerID=8YFLogxK

U2 - 10.1152/ajprenal.00449.2012

DO - 10.1152/ajprenal.00449.2012

M3 - Article

C2 - 22993073

AN - SCOPUS:84871295157

VL - 303

JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

SN - 1931-857X

IS - 12

ER -