Microvascular dysfunction after transient high glucose is caused by superoxide-dependent reduction in the bioavailability of NO and BH 4

Zsolt Bagi, Erika Toth, Akos Koller, Gabor Kaley

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Abstract

We hypothesized that transient high-glucose concentration interferes with mediation by nitric oxide (NO) of flow-induced dilation (FID) of arterioles due to enhanced production of superoxide. In isolated, pressurized (80 mmHg) rat gracilis muscle arterioles (∼130 μm) after transient high-glucose treatment (tHG; incubation with 30 mM glucose for 1 h), FID was reduced (maximum: control, 38 ± 4%; after tHG, 17 ± 3%), which was not further diminished by the NO synthase (NOS) inhibitor N ω -nitro- L-arginine methyl ester (L-NAME; 18 ± 2%). Correspondingly, an enhanced polyethylene-glycol-SOD (PEG-SOD)-sensitive superoxide production was detected after tHG in carotid arteries by dihydroethydine (DHE) staining. Presence of PEG-SOD during tHG prevented the reduction of FID (41 ± 3%), which could be inhibited by L-NAME (20 ± 4%). Administration of PEG-SOD after tHG did not prevent the reduction of FID (22 ± 3%). Sepiapterin, a precursor of the NO synthase cofactor tetrahydrobiopterin (BH 4 ), administered during tHG did not prevent the reduction of FID (maximum, 15 ± 5%); however, it restored FID when administered after tHG (32 ± 4%). Furthermore, inhibition of either glycolysis by 2-deoxyglucose or mitochondrial complex II by 2-thenoyltrifluoroacetone reduced the tHG-induced DHE-detectable enhanced superoxide production in carotid arteries and prevented FID reduction in arterioles (39 ± 5 and 35 ± 2%). Collectively, these findings suggest that in skeletal muscle arterioles, a transient elevation of glucose via its increased metabolism, elicits enhanced production of superoxide, which decreases the bioavailability of NO and the level of the NOS cofactor BH 4 , resulting in a reduction of FID mediated by NO.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume287
Issue number2 56-2
DOIs
StatePublished - Aug 1 2004
Externally publishedYes

Fingerprint

Superoxides
Biological Availability
Dilatation
Nitric Oxide
Glucose
Arterioles
Nitric Oxide Synthase
NG-Nitroarginine Methyl Ester
Carotid Arteries
Thenoyltrifluoroacetone
Deoxyglucose
Glycolysis
Skeletal Muscle
Staining and Labeling

Keywords

  • 2-deoxyglucose
  • Arteriole
  • Glycolysis
  • Mitochondrial complex II

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

@article{f489763016114ab4a9d98436deb5a987,
title = "Microvascular dysfunction after transient high glucose is caused by superoxide-dependent reduction in the bioavailability of NO and BH 4",
abstract = "We hypothesized that transient high-glucose concentration interferes with mediation by nitric oxide (NO) of flow-induced dilation (FID) of arterioles due to enhanced production of superoxide. In isolated, pressurized (80 mmHg) rat gracilis muscle arterioles (∼130 μm) after transient high-glucose treatment (tHG; incubation with 30 mM glucose for 1 h), FID was reduced (maximum: control, 38 ± 4{\%}; after tHG, 17 ± 3{\%}), which was not further diminished by the NO synthase (NOS) inhibitor N ω -nitro- L-arginine methyl ester (L-NAME; 18 ± 2{\%}). Correspondingly, an enhanced polyethylene-glycol-SOD (PEG-SOD)-sensitive superoxide production was detected after tHG in carotid arteries by dihydroethydine (DHE) staining. Presence of PEG-SOD during tHG prevented the reduction of FID (41 ± 3{\%}), which could be inhibited by L-NAME (20 ± 4{\%}). Administration of PEG-SOD after tHG did not prevent the reduction of FID (22 ± 3{\%}). Sepiapterin, a precursor of the NO synthase cofactor tetrahydrobiopterin (BH 4 ), administered during tHG did not prevent the reduction of FID (maximum, 15 ± 5{\%}); however, it restored FID when administered after tHG (32 ± 4{\%}). Furthermore, inhibition of either glycolysis by 2-deoxyglucose or mitochondrial complex II by 2-thenoyltrifluoroacetone reduced the tHG-induced DHE-detectable enhanced superoxide production in carotid arteries and prevented FID reduction in arterioles (39 ± 5 and 35 ± 2{\%}). Collectively, these findings suggest that in skeletal muscle arterioles, a transient elevation of glucose via its increased metabolism, elicits enhanced production of superoxide, which decreases the bioavailability of NO and the level of the NOS cofactor BH 4 , resulting in a reduction of FID mediated by NO.",
keywords = "2-deoxyglucose, Arteriole, Glycolysis, Mitochondrial complex II",
author = "Zsolt Bagi and Erika Toth and Akos Koller and Gabor Kaley",
year = "2004",
month = "8",
day = "1",
doi = "10.1152/ajpheart.00074.2004",
language = "English (US)",
volume = "287",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
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TY - JOUR

T1 - Microvascular dysfunction after transient high glucose is caused by superoxide-dependent reduction in the bioavailability of NO and BH 4

AU - Bagi, Zsolt

AU - Toth, Erika

AU - Koller, Akos

AU - Kaley, Gabor

PY - 2004/8/1

Y1 - 2004/8/1

N2 - We hypothesized that transient high-glucose concentration interferes with mediation by nitric oxide (NO) of flow-induced dilation (FID) of arterioles due to enhanced production of superoxide. In isolated, pressurized (80 mmHg) rat gracilis muscle arterioles (∼130 μm) after transient high-glucose treatment (tHG; incubation with 30 mM glucose for 1 h), FID was reduced (maximum: control, 38 ± 4%; after tHG, 17 ± 3%), which was not further diminished by the NO synthase (NOS) inhibitor N ω -nitro- L-arginine methyl ester (L-NAME; 18 ± 2%). Correspondingly, an enhanced polyethylene-glycol-SOD (PEG-SOD)-sensitive superoxide production was detected after tHG in carotid arteries by dihydroethydine (DHE) staining. Presence of PEG-SOD during tHG prevented the reduction of FID (41 ± 3%), which could be inhibited by L-NAME (20 ± 4%). Administration of PEG-SOD after tHG did not prevent the reduction of FID (22 ± 3%). Sepiapterin, a precursor of the NO synthase cofactor tetrahydrobiopterin (BH 4 ), administered during tHG did not prevent the reduction of FID (maximum, 15 ± 5%); however, it restored FID when administered after tHG (32 ± 4%). Furthermore, inhibition of either glycolysis by 2-deoxyglucose or mitochondrial complex II by 2-thenoyltrifluoroacetone reduced the tHG-induced DHE-detectable enhanced superoxide production in carotid arteries and prevented FID reduction in arterioles (39 ± 5 and 35 ± 2%). Collectively, these findings suggest that in skeletal muscle arterioles, a transient elevation of glucose via its increased metabolism, elicits enhanced production of superoxide, which decreases the bioavailability of NO and the level of the NOS cofactor BH 4 , resulting in a reduction of FID mediated by NO.

AB - We hypothesized that transient high-glucose concentration interferes with mediation by nitric oxide (NO) of flow-induced dilation (FID) of arterioles due to enhanced production of superoxide. In isolated, pressurized (80 mmHg) rat gracilis muscle arterioles (∼130 μm) after transient high-glucose treatment (tHG; incubation with 30 mM glucose for 1 h), FID was reduced (maximum: control, 38 ± 4%; after tHG, 17 ± 3%), which was not further diminished by the NO synthase (NOS) inhibitor N ω -nitro- L-arginine methyl ester (L-NAME; 18 ± 2%). Correspondingly, an enhanced polyethylene-glycol-SOD (PEG-SOD)-sensitive superoxide production was detected after tHG in carotid arteries by dihydroethydine (DHE) staining. Presence of PEG-SOD during tHG prevented the reduction of FID (41 ± 3%), which could be inhibited by L-NAME (20 ± 4%). Administration of PEG-SOD after tHG did not prevent the reduction of FID (22 ± 3%). Sepiapterin, a precursor of the NO synthase cofactor tetrahydrobiopterin (BH 4 ), administered during tHG did not prevent the reduction of FID (maximum, 15 ± 5%); however, it restored FID when administered after tHG (32 ± 4%). Furthermore, inhibition of either glycolysis by 2-deoxyglucose or mitochondrial complex II by 2-thenoyltrifluoroacetone reduced the tHG-induced DHE-detectable enhanced superoxide production in carotid arteries and prevented FID reduction in arterioles (39 ± 5 and 35 ± 2%). Collectively, these findings suggest that in skeletal muscle arterioles, a transient elevation of glucose via its increased metabolism, elicits enhanced production of superoxide, which decreases the bioavailability of NO and the level of the NOS cofactor BH 4 , resulting in a reduction of FID mediated by NO.

KW - 2-deoxyglucose

KW - Arteriole

KW - Glycolysis

KW - Mitochondrial complex II

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JO - American Journal of Physiology - Heart and Circulatory Physiology

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