Red wine polyphenols prevent endothelial dysfunction induced by endothelin-1 in rat aorta: role of NADPH oxidase.
RWPs (red wine polyphenols) exert antihypertensive effects and improve endothelial function by reducing the plasma levels of ET-1 (endothelin-1) and the subsequent vascular production of O(2)(•-) (superoxide anion). Our present study was designed to evaluate whether RWPs act directly in the vascular wall improving endothelial dysfunction and O(2)(•-) production induced by ET-1 and to analyse the compounds responsible for these protective effects. We incubated rat isolated aortic rings in the presence or absence of ET-1 (10 nM) and RWPs (10(-4) to 10(-2) g/l) or catechin (0.2 μM), epicatechin (10 μM) and resveratrol (0.1 μM). ET-1 reduced the relaxant responses to acetylcholine, increased intracellular O(2)(•-) production, NADPH oxidase activity and protein expression of NADPH oxidase subunit p47phox. All these changes were prevented by RWPs. The preventive effects of RWPs were unaffected by co-incubation with either ICI-182780, an ER (oestrogen receptor) antagonist, or GW9662, a PPARγ (peroxisome-proliferator-activated receptor γ) antagonist. RWPs inhibited the phosphorylation of the mitogen-activated protein kinase, ERK1/2 (extracellular signal-regulated kinase 1/2), a key regulator of p47phox expression in response to ET-1. When the isolated polyphenols were tested, at the concentrations found in 10(-2) g/l RWPs, only epicatechin prevented endothelial dysfunction and all biochemical changes induced by ET-1 in the vascular wall. Taken together, these results indicate that RWPs prevent ET-1-induced vascular O(2)(•-) production by reducing overexpression of p47phox and the subsequent increased NADPH oxidase activity, leading to improvement in endothelial function. The effects of RWPs appear to be independent of ER and PPARγ activation and are related to ERK1/2 inhibition.
Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain.
Rocío
R
López-Sepúlveda
Manuel
M
Gómez-Guzmán
Maria José
MJ
Zarzuelo
Miguel
M
Romero
Manuel
M
Sánchez
Ana María
AM
Quintela
Pilar
P
Galindo
Francisco
F
O'Valle
Juan
J
Tamargo
Francisco
F
Pérez-Vizcaíno
Juan
J
Duarte
Rosario
R
Jiménez
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D005419:Flavonoids / Q000494:pharmacology*; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D059808:Polyphenols; D051381:Rats; D017208:Rats, Wistar; D046509:Tissue Culture Techniques; D014661:Vasoconstriction / Q000187:drug effects; D014920:Wine / Q000032:analysis*
D000959:Antihypertensive Agents; D019332:Endothelin-1; D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D009569:Nitric Oxide; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D010100:Oxygen