Targeted and persistent effects of NO mediated by S-nitrosation of tissue thiols in arteries with endothelial dysfunction.
We have previously demonstrated that in endothelium-denuded arteries, S-nitrosation of cysteine residues is a mechanism of formation of releasable nitric oxide (NO) stores, accounting for the long-lasting relaxation induced by S-nitrosating agents like S-nitrosoglutathione (GSNO). Here, we have investigated whether such effects could also be obtained in arteries exhibiting oxidative stress-associated endothelial dysfunction. Rats were implanted or not with a minipump delivering saline or angiotensin II for 14 days. As expected, aorta from angiotensin II-infused rats exhibited increased level of superoxide anions (as evaluated with dihydroethidine as fluorescent probe) and a reduced relaxation to acetylcholine in comparison to saline group. Unlike aortic rings with endothelium from controls, those from angiotensin II-infused rats exhibited persistent hyporesponsiveness to phenylephrine after pre-exposure to GSNO, as well as relaxation upon addition of N-acetylcysteine (NAC, which can displace NO from cysteine-NO residues) or HgCl(2) (which cleaves S-NO bonds). In aorta from angiotensin II-infused rats, GSNO also induced a persistent increase in cysteine-NO residues (as determined using anti-cysteine-NO antiserum), which was blunted by NAC and HgCl(2). These data indicate that (i) the vasorelaxant influence of releasable NO stores is unmasked by endothelial dysfunction (ii) S-nitrosation of cysteine residues remains an effective mechanism of formation of releasable NO stores in arteries exhibited oxidative stress-associated endothelial dysfunction. Thus, formation of releasable NO stores by S-nitrosating agents allows targeted vasculoprotective effects of NO at sites of endothelial dysfunction.
Sarr
Mamadou
M
Pharmacologie & Physico-Chimie, UMR CNRS 7175 LC1, BP 60024, F-67401 Illkirch.
Chataigneau
Marta
M
Etienne-Selloum
Nelly
N
Diallo
Aminata S
AS
Schott
Christa
C
Geffard
Michel
M
Stoclet
Jean-Claude
JC
Schini-Kerth
Valérie B
VB
Muller
Bernard
B
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000838:Anions; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008954:Models, Biological; D019331:NG-Nitroarginine Methyl Ester / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009584:Nitrogen / Q000737:chemistry*; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds / Q000737:chemistry*
D000838:Anions; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D000804:Angiotensin II; D009569:Nitric Oxide; D003545:Cysteine; D009584:Nitrogen; D019331:NG-Nitroarginine Methyl Ester