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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/H2508    most recent 00352.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Gendron, M.-E. Articles by Thorin, E. Search for Related Content PubMed PubMed Citation Articles by Gendron, M.-E. Articles by Thorin, E.

A change in the redox environment and thromboxane A₂ production precede endothelial dysfunction in mice

Departments of ¹Physiology and ²Surgery, Faculty of Medicine, Université de Montréal, Montreal Heart Institute, Montreal, Quebec, Canada

Submitted 20 March 2007 ; accepted in final form 16 July 2007

We reported that the endothelial dysfunction that develops with age was associated with a proinflammatory phenotype. In this study, we hypothesized that an increased production of proinflammatory cyclooxygenase (COX) products occurs before endothelial dysfunction. Dilations to acetylcholine (ACh) were recorded from pressurized renal arteries isolated from 3- and 6-mo-old C57Bl/6 male mice treated or not with the polyphenol catechin (30 mg·kg^–1·day^–1) in drinking water for 3 mo. Release of thromboxane (TX) B₂, the metabolite of TXA₂, was measured by using immunoenzymatic assays, and free radical production was measured by using the fluorescent dye CM-H₂DCFDA. Endothelial nitric oxide synthase (eNOS) and COX-1/2 mRNA expression were quantified by quantitative PCR. N^G-nitro-L-arginine (L-NNA) reduced (P < 0.05) ACh-induced dilation in vessels isolated from 3- and 6-mo-old mice. In the presence of L-NNA, indomethacin normalized (P < 0.05) the dilation in vessels from 6-mo-old mice only. SQ-29548 (PGH₂/TXA₂ receptor antagonist) and furegrelate (TXA₂ synthase inhibitor), in the presence of L-NNA, also improved (P < 0.05) dilation. L-NNA increased TXA₂ release and free radical-associated fluorescence, the latter being prevented by SQ-29548. In vessels from 6-mo-old mice treated with catechin for 3 mo, L-NNA-dependent reduction in ACh-mediated dilation was insensitive to indomethacin, whereas TXA₂ release and free radical-associated fluorescence were prevented. eNOS mRNA expression was significantly increased by catechin treatment. Our results suggest that an augmented production of TXA₂ and the associated change in redox regulation precede the development of the endothelial dysfunction.

nitric oxide; cyclooxygenase; reactive oxygen species