Augmented oxidative stress and preserved vasoconstriction induced by hydrogen peroxide in coronary arteries in obesity: role of COX-2

作者：Santiago Elvira; Pilar Martinez Maria; Climent Belen; Munoz Mercedes; Maria Briones Ana; Salaices Mercedes; Garcia Sacristan Albino; Rivera Luis; Prieto Dolores^*

来源：British Journal of Pharmacology, 2016, 173(22): 3176-3195.

DOI：10.1111/bph.13579

BACKGROUND AND PURPOSE
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 (O-2(center dot-)) generation.
EXPERIMENTAL APPROACH
Contractile responses to H2O2 and O-2(center dot-) generation were measured in coronary arteries from genetically obese Zucker rats (OZR) and compared to lean Zucker rats (LZR).
KEY RESULTS
Both basal and H2O2-stimulated O-2(center dot-) 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. PGI(2) (IP) receptor antagonism modestly reduced the vasoconstrictor action of H2O2 while antagonism of the PGE2 receptor 4 (EP4) enhanced H2O2 contractions in arteries from OZR but not LZR. Basal release of COX-2-derived PGE2 was higher in coronary arteries from OZR where the selective agonist of EP4 receptors TCS 2519 evoked potent relaxations. COX-2 was up-regulated after acute exposure to H2O2 in coronary endothelium and vascular smooth muscle (VSM) and inhibition of COX-2 markedly reduced H2O2-elicited O-2(center dot-) generation in coronary arteries and myocardium. Expression of Nox subunits in VSM and NADPH-stimulated O-2(center dot-) generation was enhanced and contributed to H2O2 vasoconstriction in arteries from obese rats.
CONCLUSION AND IMPLICATIONS
COX-2 contributes to cardiac oxidative stress and to the endothelium-independent O-2(center dot-)-mediated coronary vasoconstriction induced by H2O2 in obesity, which is offset by the release of COX-2-derived endothelial PGE2 acting on EP4 vasodilator receptors.

• 出版日期2016-11