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 2 O 2 ) and the signalling pathways involving COX‐2 and superoxide (O 2 .‐ ) generation. Experimental Approach Contractile responses to H 2 O 2 and O 2 .‐ 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 2 O 2 ‐stimulated O 2 .‐ production were enhanced in coronary arteries from OZR, but H 2 O 2 ‐induced vasoconstriction was unchanged. The selective COX‐2 inhibitor NS398 significantly reduced H 2 O 2 ‐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 H 2 O 2 while antagonism of the PGE 2 receptor 4 (EP 4 ) enhanced H 2 O 2 contractions in arteries from OZR but not LZR. Basal release of COX‐2‐derived PGE 2 was higher in coronary arteries from OZR where the selective agonist of EP 4 receptors TCS 2519 evoked potent relaxations. COX‐2 was up‐regulated after acute exposure to H 2 O 2 in coronary endothelium and vascular smooth muscle (VSM) and inhibition of COX‐2 markedly reduced H 2 O 2 ‐elicited O 2 .‐ generation in coronary arteries and myocardium. Expression of Nox subunits in VSM and NADPH‐stimulated O 2 .‐ generation was enhanced and contributed to H 2 O 2 vasoconstriction in arteries from obese rats. Conclusion and Implications COX‐2 contributes to cardiac oxidative stress and to the endothelium‐independent O 2 .‐ ‐mediated coronary vasoconstriction induced by H 2 O 2 in obesity, which is offset by the release of COX‐2‐derived endothelial PGE 2 acting on EP 4 vasodilator receptors.