Augmented S-nitrosylation contributes to impaired relaxation in angiotensin II hypertensive mouse aorta: Role of thioredoxin reductase

Hyehun Choi, Kyan J. Allahdadi, Rita C. Tostes, R. Clinton Webb

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Vascular dysfunction, including reduced endothelium-dependent dilation, is a major characteristic of hypertension. We previously investigated that thioredoxin reductase (TrxR) inhibition impairs vasodilation via soluble guanylyl cyclase S-nitrosylation, but S-nitrosylation and TrxR function are not known in hypertension. We hypothesized that S-nitrosylation is associated with reduced vasodilation in hypertensive mice. METHOD: Aortic rings from normotensive (sham) and angiotensin II (AngII)-induced hypertensive C57BL/6 mice were treated with a TrxR inhibitor, 1-chloro-2,4-dinitrobenzene (DNCB) for 30 min, and relaxation to acetylcholine (ACh) was measured in the rings following contraction with phenylephrine. RESULTS: DCNB reduced relaxation to ACh compared with vehicle in sham aorta but not in AngII (sham-vehicle Emax=77 ± 2, sham-DNCB Emax=59 ± 4, P < 0.05). DNCB shifted the concentration-response relaxation to sodium nitroprusside (SNP) to the right in both sham and AngII aortic rings (sham-vehicle pD2=8.8±0.1, sham-DNCB pD2=8.4±0.1, *P < 0.05; AngII-vehicle pD2=8.5±0.1, AngII-DNCB pD2=8.3 ± 0.1, P < 0.05). As downstream signaling of nitric oxide, cyclic GMP level was reduced by DNCB during activation with SNP. The effect of DNCB to increase S-nitrosylation was confirmed by the biotin-switch method and western blot analysis, and total protein S-nitrosylation was increased in AngII aorta (1.5-fold) compared with sham. TrxR activity was inhibited in AngII aorta compared with sham. CONCLUSION: We conclude that increased S-nitrosylation contributes to impaired relaxation in aorta from AngII-induced hypertensive mice. AngII treatment resulted in inactivation of TrxR and increased S-nitrosylation, indicating that TrxR and S-nitrosylation may provide a critical mechanism in hypertension associated with abnormal vascular reactivity.

Original languageEnglish (US)
Pages (from-to)2359-2368
Number of pages10
JournalJournal of hypertension
Volume29
Issue number12
DOIs
StatePublished - Dec 1 2011

Fingerprint

Thioredoxin-Disulfide Reductase
Dinitrochlorobenzene
Angiotensin II
Aorta
Nitroprusside
Hypertension
Vasodilation
Acetylcholine
Blood Vessels
Thioredoxin Reductase 1
Protein S
Cyclic GMP
Phenylephrine
Biotin
Inbred C57BL Mouse
Endothelium
Dilatation
Nitric Oxide
Western Blotting

Keywords

  • Hypertension
  • S-nitrosylation
  • thioredoxin reductase
  • vascular relaxation

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Augmented S-nitrosylation contributes to impaired relaxation in angiotensin II hypertensive mouse aorta : Role of thioredoxin reductase. / Choi, Hyehun; Allahdadi, Kyan J.; Tostes, Rita C.; Webb, R. Clinton.

In: Journal of hypertension, Vol. 29, No. 12, 01.12.2011, p. 2359-2368.

Research output: Contribution to journalArticle

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abstract = "BACKGROUND: Vascular dysfunction, including reduced endothelium-dependent dilation, is a major characteristic of hypertension. We previously investigated that thioredoxin reductase (TrxR) inhibition impairs vasodilation via soluble guanylyl cyclase S-nitrosylation, but S-nitrosylation and TrxR function are not known in hypertension. We hypothesized that S-nitrosylation is associated with reduced vasodilation in hypertensive mice. METHOD: Aortic rings from normotensive (sham) and angiotensin II (AngII)-induced hypertensive C57BL/6 mice were treated with a TrxR inhibitor, 1-chloro-2,4-dinitrobenzene (DNCB) for 30 min, and relaxation to acetylcholine (ACh) was measured in the rings following contraction with phenylephrine. RESULTS: DCNB reduced relaxation to ACh compared with vehicle in sham aorta but not in AngII (sham-vehicle Emax=77 ± 2, sham-DNCB Emax=59 ± 4, P < 0.05). DNCB shifted the concentration-response relaxation to sodium nitroprusside (SNP) to the right in both sham and AngII aortic rings (sham-vehicle pD2=8.8±0.1, sham-DNCB pD2=8.4±0.1, *P < 0.05; AngII-vehicle pD2=8.5±0.1, AngII-DNCB pD2=8.3 ± 0.1, P < 0.05). As downstream signaling of nitric oxide, cyclic GMP level was reduced by DNCB during activation with SNP. The effect of DNCB to increase S-nitrosylation was confirmed by the biotin-switch method and western blot analysis, and total protein S-nitrosylation was increased in AngII aorta (1.5-fold) compared with sham. TrxR activity was inhibited in AngII aorta compared with sham. CONCLUSION: We conclude that increased S-nitrosylation contributes to impaired relaxation in aorta from AngII-induced hypertensive mice. AngII treatment resulted in inactivation of TrxR and increased S-nitrosylation, indicating that TrxR and S-nitrosylation may provide a critical mechanism in hypertension associated with abnormal vascular reactivity.",
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T1 - Augmented S-nitrosylation contributes to impaired relaxation in angiotensin II hypertensive mouse aorta

T2 - Role of thioredoxin reductase

AU - Choi, Hyehun

AU - Allahdadi, Kyan J.

AU - Tostes, Rita C.

AU - Webb, R. Clinton

PY - 2011/12/1

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N2 - BACKGROUND: Vascular dysfunction, including reduced endothelium-dependent dilation, is a major characteristic of hypertension. We previously investigated that thioredoxin reductase (TrxR) inhibition impairs vasodilation via soluble guanylyl cyclase S-nitrosylation, but S-nitrosylation and TrxR function are not known in hypertension. We hypothesized that S-nitrosylation is associated with reduced vasodilation in hypertensive mice. METHOD: Aortic rings from normotensive (sham) and angiotensin II (AngII)-induced hypertensive C57BL/6 mice were treated with a TrxR inhibitor, 1-chloro-2,4-dinitrobenzene (DNCB) for 30 min, and relaxation to acetylcholine (ACh) was measured in the rings following contraction with phenylephrine. RESULTS: DCNB reduced relaxation to ACh compared with vehicle in sham aorta but not in AngII (sham-vehicle Emax=77 ± 2, sham-DNCB Emax=59 ± 4, P < 0.05). DNCB shifted the concentration-response relaxation to sodium nitroprusside (SNP) to the right in both sham and AngII aortic rings (sham-vehicle pD2=8.8±0.1, sham-DNCB pD2=8.4±0.1, *P < 0.05; AngII-vehicle pD2=8.5±0.1, AngII-DNCB pD2=8.3 ± 0.1, P < 0.05). As downstream signaling of nitric oxide, cyclic GMP level was reduced by DNCB during activation with SNP. The effect of DNCB to increase S-nitrosylation was confirmed by the biotin-switch method and western blot analysis, and total protein S-nitrosylation was increased in AngII aorta (1.5-fold) compared with sham. TrxR activity was inhibited in AngII aorta compared with sham. CONCLUSION: We conclude that increased S-nitrosylation contributes to impaired relaxation in aorta from AngII-induced hypertensive mice. AngII treatment resulted in inactivation of TrxR and increased S-nitrosylation, indicating that TrxR and S-nitrosylation may provide a critical mechanism in hypertension associated with abnormal vascular reactivity.

AB - BACKGROUND: Vascular dysfunction, including reduced endothelium-dependent dilation, is a major characteristic of hypertension. We previously investigated that thioredoxin reductase (TrxR) inhibition impairs vasodilation via soluble guanylyl cyclase S-nitrosylation, but S-nitrosylation and TrxR function are not known in hypertension. We hypothesized that S-nitrosylation is associated with reduced vasodilation in hypertensive mice. METHOD: Aortic rings from normotensive (sham) and angiotensin II (AngII)-induced hypertensive C57BL/6 mice were treated with a TrxR inhibitor, 1-chloro-2,4-dinitrobenzene (DNCB) for 30 min, and relaxation to acetylcholine (ACh) was measured in the rings following contraction with phenylephrine. RESULTS: DCNB reduced relaxation to ACh compared with vehicle in sham aorta but not in AngII (sham-vehicle Emax=77 ± 2, sham-DNCB Emax=59 ± 4, P < 0.05). DNCB shifted the concentration-response relaxation to sodium nitroprusside (SNP) to the right in both sham and AngII aortic rings (sham-vehicle pD2=8.8±0.1, sham-DNCB pD2=8.4±0.1, *P < 0.05; AngII-vehicle pD2=8.5±0.1, AngII-DNCB pD2=8.3 ± 0.1, P < 0.05). As downstream signaling of nitric oxide, cyclic GMP level was reduced by DNCB during activation with SNP. The effect of DNCB to increase S-nitrosylation was confirmed by the biotin-switch method and western blot analysis, and total protein S-nitrosylation was increased in AngII aorta (1.5-fold) compared with sham. TrxR activity was inhibited in AngII aorta compared with sham. CONCLUSION: We conclude that increased S-nitrosylation contributes to impaired relaxation in aorta from AngII-induced hypertensive mice. AngII treatment resulted in inactivation of TrxR and increased S-nitrosylation, indicating that TrxR and S-nitrosylation may provide a critical mechanism in hypertension associated with abnormal vascular reactivity.

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