Journal
HYPERTENSION
Volume 51, Issue 4, Pages 872-877Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.107.103572
Keywords
oxidative stress; hydrogen peroxide; genetically altered mice; carotid arteries; endothelium
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Funding
- NHLBI NIH HHS [HL-63943, HL-62984, R01 HL063943, HL-38901, P01 HL062984, R01 HL038901, R01 HL038901-21] Funding Source: Medline
- NINDS NIH HHS [P01 NS024621, P01 NS024621-21A1, NS-24621] Funding Source: Medline
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Levels of reactive oxygen species, including hydrogen peroxide, increase in blood vessels during hypertension and in response to angiotensin II (Ang II). Although glutathione peroxidases are known to metabolize hydrogen peroxide, the role of glutathione peroxidase during hypertension is poorly defined. We tested the hypothesis that glutathione peroxidase-1 protects against Ang II-induced endothelial dysfunction. Responses of carotid arteries from Gpx1-deficient (Gpx1(+/-) and Gpx1(-/-)) and Gpx1 transgenic mice, and their respective littermate controls, were examined in vitro after overnight incubation with either vehicle or Ang II. Under control conditions, relaxation to acetylcholine (ACh; an endothelium-dependent agonist) was similar in control, Gpx1(-/-), and Gpx1 transgenic mice, whereas in Gpx1(-/-) mice, responses to ACh were impaired. In control mice, ACh-induced vasorelaxation was not affected by 1 nmol/L of Ang II. In contrast, relaxation to ACh in arteries from Gpx1(-/-) mice was inhibited by approximate to 60% after treatment with 1 nmol/L of Ang II, indicating that Gpx1 haploinsufficiency markedly enhances Ang II-induced endothelial dysfunction. A higher concentration of Ang II ( 10 nmol/L) selectively impaired relaxation to ACh in arteries from control mice, and this effect was prevented in arteries from Gpx1 transgenic mice or in arteries from control mice treated with polyethylene glycol-catalase ( which degrades hydrogen peroxide). Thus, genetic and pharmacological evidence suggests a major role for glutathione peroxidase-1 and hydrogen peroxide in Ang II-induced effects on vascular function.
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