title: Cyclooxygenase-1 is involved in endothelial dysfunction of mesenteric small arteries from angiotensin II-infused mice.
abstract: Angiotensin II induces endothelial dysfunction by reducing NO availability and increasing reactive oxygen species. We assessed whether cyclooxygenase (COX)-1 or COX-2 participate in the angiotensin II-induced endothelial dysfunction in murine mesenteric small arteries and examined the role of reduced nicotinamide-adenine dinucleotide phosphate-dependent reactive oxygen species production. Mice received angiotensin II (600 ng/kg per minute, SC), saline (controls), angiotensin II + apocynin (reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor, 2.5 mg/day), or apocynin alone for 2 weeks. Endothelial function of mesenteric arteries was assessed by pressurized myograph. In controls, acetylcholine-induced relaxation was inhibited by NG-monomethyl-L-arginine and unaffected by DFU (COX-2 inhibitor), SC-560 (COX-1 inhibitor), or ascorbic acid. In angiotensin II-infused animals, the attenuated response to acetylcholine was less sensitive to NG-monomethyl-L-arginine, unaffected by DFU, and enhanced by SC-560 and, similarly, by SQ-29548, a thromboxane-prostanoid receptor antagonist. Moreover, response to acetylcholine was unchanged by ozagrel, a thromboxane synthase inhibitor, and normalized by ascorbic acid. Apocynin prevented the angiotensin II-induced vascular dysfunctions. In angiotensin II-infused mice, RT-PCR analysis showed a significant COX-2 downregulation, whereas COX-1 expression was upregulated. These changes were unaffected by apocynin. Modulation of COX isoform by angiotensin II was also documented by immunohistochemistry. In small mesenteric vessels, the reduced NO availability and oxidant excess, which characterize endothelial dysfunction secondary to angiotensin II, are associated with a reduced COX-2 and an increased COX-1 function and expression. Angiotensin II causes an oxidative stress-independent COX-1 overexpression, whereas angiotensin II-mediated oxidant excess production stimulates COX-1 activity to produce a contracting prostanoid endowed with agonist activity on thromboxane-prostanoid receptors.
authors.affiliation: Department of Internal Medicine, University of Pisa, Pisa, Italy. a.virdis@med.unipi.it
authors.forename: Agostino
authors.initials: A
authors.lastname: Virdis
authors.forename: Rocchina
authors.initials: R
authors.lastname: Colucci
authors.forename: Matteo
authors.initials: M
authors.lastname: Fornai
authors.forename: Emiliano
authors.initials: E
authors.lastname: Duranti
authors.forename: Chiara
authors.initials: C
authors.lastname: Giannarelli
authors.forename: Nunzia
authors.initials: N
authors.lastname: Bernardini
authors.forename: Cristina
authors.initials: C
authors.lastname: Segnani
authors.forename: Chiara
authors.initials: C
authors.lastname: Ippolito
authors.forename: Luca
authors.initials: L
authors.lastname: Antonioli
authors.forename: Corrado
authors.initials: C
authors.lastname: Blandizzi
authors.forename: Stefano
authors.initials: S
authors.lastname: Taddei
authors.forename: Antonio
authors.initials: A
authors.lastname: Salvetti
authors.forename: Mario
authors.initials: M
authors.lastname: Del Tacca
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D051545:Cyclooxygenase 1 / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000503:physiopathology; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; D019255:NADPH Oxidases