title: Augmented oxidative stress and preserved vasoconstriction induced by hydrogen peroxide in coronary arteries in obesity: role of COX-2.
abstract: Oxidative stress plays a key role in the vascular and metabolic abnormalities associated with obesity. Herein, we assessed whether obesity can increase coronary vasoconstriction induced by hydrogen peroxide (H2O2) and the signalling pathways involving COX-2 and superoxide (O2.-) generation.
  
  
  
  Contractile responses to H2O2and O2.-generation were measured in coronary arteries from genetically obese Zucker rats (OZR) and compared to lean Zucker rats (LZR).
  
  
  
  Both basal and H2O2-stimulated O2.-production were enhanced in coronary arteries from OZR, but H2O2-induced vasoconstriction was unchanged. The selective COX-2 inhibitor NS398 significantly reduced H2O2-induced contractions in endothelium-denuded arteries from LZR and OZR, but only in endothelium-intact arteries from LZR. PGI2(IP) receptor antagonism modestly reduced the vasoconstrictor action of H2O2while antagonism of the PGE2receptor 4 (EP4) enhanced H2O2contractions in arteries from OZR but not LZR. Basal release of COX-2-derived PGE2was higher in coronary arteries from OZR where the selective agonist of EP4receptors TCS 2519 evoked potent relaxations. COX-2 was up-regulated after acute exposure to H2O2in coronary endothelium and vascular smooth muscle (VSM) and inhibition of COX-2 markedly reduced H2O2-elicited O2.-generation in coronary arteries and myocardium. Expression of Nox subunits in VSM and NADPH-stimulated O2.-generation was enhanced and contributed to H2O2vasoconstriction in arteries from obese rats.
  
  
  
  COX-2 contributes to cardiac oxidative stress and to the endothelium-independent O2.--mediated coronary vasoconstriction induced by H2O2in obesity, which is offset by the release of COX-2-derived endothelial PGE2acting on EP4vasodilator receptors.
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Elvira
authors.initials: E
authors.lastname: Santiago
authors.affiliation: Departamento de Anatomía and Anatomía Patológica Comparadas, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Maria Pilar
authors.initials: MP
authors.lastname: Martínez
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Climent
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Muñoz
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Ana María
authors.initials: AM
authors.lastname: Briones
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Salaices
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Albino
authors.initials: A
authors.lastname: García-Sacristán
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Rivera
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain. dprieto@ucm.es.
authors.forename: Dolores
authors.initials: D
authors.lastname: Prieto
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008297:Male; D009765:Obesity / Q000201:enzymology / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D011924:Rats, Zucker; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D006861:Hydrogen Peroxide; D051546:Cyclooxygenase 2