A change in the redox environment and thromboxane A2 production precede endothelial dysfunction in mice.
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 x kg(-1) x day(-1)) in drinking water for 3 mo. Release of thromboxane (TX) B(2), the metabolite of TXA(2), was measured by using immunoenzymatic assays, and free radical production was measured by using the fluorescent dye CM-H(2)DCFDA. 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 (PGH(2)/TXA(2) receptor antagonist) and furegrelate (TXA(2) synthase inhibitor), in the presence of L-NNA, also improved (P < 0.05) dilation. L-NNA increased TXA(2) 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 TXA(2) 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 TXA(2) and the associated change in redox regulation precede the development of the endothelial dysfunction.
Gendron
Marie-Eve
ME
Department of Physiology, Faculty of Medicine, Université de Montréal, Montreal Heart Institute, Montreal, Quebec, Canada.
Thorin
Eric
E
D000109:Acetylcholine / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000375:Aging / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002392:Catechin / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006834:Hydrazines / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000494:pharmacology; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012077:Renal Artery / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D013928:Thromboxane A2 / Q000378:metabolism*; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D000975:Antioxidants; D001572:Benzofurans; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D008565:Membrane Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014665:Vasodilator Agents; D019335:Nitroarginine; D009569:Nitric Oxide; D013929:Thromboxane B2; D013928:Thromboxane A2; C045749:SQ 29548; D002392:Catechin; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D013930:Thromboxane-A Synthase; C039936:furegrelate; D000109:Acetylcholine; D000111:Acetylcysteine; D007213:Indomethacin