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 language | English (US) |
|---|---|
| Journal | American Journal of Physiology - Renal Physiology |
| Volume | 303 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 15 2012 |
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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 journal › Article
}
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 -