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

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 (H O ) and the signalling pathways involving COX-2 and superoxide (O ) generation.

Experimental Approach: Contractile responses to H O and O generation were measured in coronary arteries from genetically obese Zucker rats (OZR) and compared to lean Zucker rats (LZR).

Key Results: Both basal and H O -stimulated O production were enhanced in coronary arteries from OZR, but H O -induced vasoconstriction was unchanged. The selective COX-2 inhibitor NS398 significantly reduced H O -induced contractions in endothelium-denuded arteries from LZR and OZR, but only in endothelium-intact arteries from LZR. PGI (IP) receptor antagonism modestly reduced the vasoconstrictor action of H O while antagonism of the PGE receptor 4 (EP ) enhanced H O contractions in arteries from OZR but not LZR. Basal release of COX-2-derived PGE was higher in coronary arteries from OZR where the selective agonist of EP receptors TCS 2519 evoked potent relaxations. COX-2 was up-regulated after acute exposure to H O in coronary endothelium and vascular smooth muscle (VSM) and inhibition of COX-2 markedly reduced H O -elicited O generation in coronary arteries and myocardium. Expression of Nox subunits in VSM and NADPH-stimulated O generation was enhanced and contributed to H O vasoconstriction in arteries from obese rats.

Conclusion And Implications: COX-2 contributes to cardiac oxidative stress and to the endothelium-independent O -mediated coronary vasoconstriction induced by H O in obesity, which is offset by the release of COX-2-derived endothelial PGE acting on EP vasodilator receptors.