We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Up-regulation of thromboxane A impairs cerebrovascular eNOS function in aging atherosclerotic mice.
- Authors
Drouin, Annick; Farhat, Nada; Bolduc, Virginie; Thorin-Trescases, Nathalie; Gillis, Marc-Antoine; Villeneuve, Louis; Nguyen, Albert; Thorin, Eric
- Abstract
We previously reported that in healthy mouse cerebral arteries, endothelial nitric oxide synthase (eNOS) produces HO, leading to endothelium-dependent dilation. In contrast, thromboxane A (TXA), a potent pro-oxidant and pro-inflammatory endogenous vasoconstrictor, is associated with eNOS dysfunction. Our objectives were to elucidate whether (1) the cerebrovascular eNOS-HO pathway was sensitive to oxidative stress associated with aging and dyslipidemia and (2) TXA contributed to cerebral eNOS dysfunction. Atherosclerotic (ATX = LDLR; hApoB) and wild-type (WT) control mice were used at 3 and 12 months old (m/o). Three-m/o ATX mice were treated with the cardio-protective polyphenol catechin for 9 months. Dilations to ACh and the simultaneous eNOS-derived HO production were recorded in isolated pressurized cerebral arteries. The age-associated decrease in cerebral eNOS-HO pathway observed in WT was premature in ATX mice, decreasing at 3 m/o and abolished at 12 m/o. Thromboxane synthase inhibition by furegrelate increased dilations at 12 months in WT and at 3 and 12 months in ATX mice, suggesting an anti-dilatory role of TXA with age hastened by dyslipidemia. In addition, the non-selective NADP(H) oxidase inhibitor apocynin improved the eNOS-HO pathway only in 12-m/o ATX mice. Catechin normalized the function of this pathway, which became sensitive to L-NNA and insensitive to furegrelate or apocynin; catechin also prevented the rise in TXA synthase expression. In conclusion, the age-dependent cerebral endothelial dysfunction is precocious in dyslipidemia and involves TXA production that limits eNOS activity. Preventive catechin treatment reduced the impact of endogenous TXA on the control of cerebral tone and maintained eNOS function.
- Subjects
GENETIC regulation; THROMBOXANES; CEREBROVASCULAR disease; ATHEROSCLEROSIS; CEREBRAL arteries; NITRIC-oxide synthases; OXIDATIVE stress; LABORATORY mice
- Publication
Pflügers Archiv: European Journal of Physiology, 2011, Vol 462, Issue 3, p371
- ISSN
0031-6768
- Publication type
Article
- DOI
10.1007/s00424-011-0973-y