Dataset Information

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

ABSTRACT:

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 (H₂ O₂ ) and the signalling pathways involving COX-2 and superoxide (O₂^.- ) generation.

Experimental approach

Contractile responses to H₂ O₂ and O₂^.- generation were measured in coronary arteries from genetically obese Zucker rats (OZR) and compared to lean Zucker rats (LZR).

Key results

Both basal and H₂ O₂ -stimulated O₂^.- production were enhanced in coronary arteries from OZR, but H₂ O₂ -induced vasoconstriction was unchanged. The selective COX-2 inhibitor NS398 significantly reduced H₂ O₂ -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 H₂ O₂ while antagonism of the PGE₂ receptor 4 (EP₄ ) enhanced H₂ O₂ 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 H₂ O₂ in coronary endothelium and vascular smooth muscle (VSM) and inhibition of COX-2 markedly reduced H₂ O₂ -elicited O₂^.- generation in coronary arteries and myocardium. Expression of Nox subunits in VSM and NADPH-stimulated O₂^.- generation was enhanced and contributed to H₂ O₂ vasoconstriction in arteries from obese rats.

Conclusion and implications

COX-2 contributes to cardiac oxidative stress and to the endothelium-independent O₂^.- -mediated coronary vasoconstriction induced by H₂ O₂ in obesity, which is offset by the release of COX-2-derived endothelial PGE₂ acting on EP₄ vasodilator receptors.

SUBMITTER: Santiago E

PROVIDER: S-EPMC5071563 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Santiago Elvira E Martínez Maria Pilar MP Climent Belén B Muñoz Mercedes M Briones Ana María AM Salaices Mercedes M García-Sacristán Albino A Rivera Luis L Prieto Dolores D

British journal of pharmacology 20161007 22

<h4>Background and purpose</h4>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<sub>2</sub> O<sub>2</sub> ) and the signalling pathways involving COX-2 and superoxide (O<sub>2</sub><sup>.-</sup> ) generation.<h4>Experimental approach</h4>Contractile responses to H<sub>2</sub> O<sub>2</sub> and O<sub>2</sub><sup>.-</sup> generation were m ...[more]

PMID: 27535007

Similar Datasets

Project description:KEY POINTS:Vascular oxidative stress increases with advancing age. We hypothesized that resistance vessels develop resilience to oxidative stress to protect functional integrity and tested this hypothesis by exposing isolated pressurized superior epigastric arteries (SEAs) of old and young mice to H2 O2 . H2 O2 -induced death was greater in smooth muscle cells (SMCs) than endothelial cells (ECs) and lower in SEAs from old vs. young mice; the rise in vessel wall [Ca2+ ]i induced by H2 O2 was attenuated with ageing, as was the decline in noradrenergic vasoconstriction; genetic deletion of IL-10 mimicked the effects of advanced age on cell survival. Inhibiting NO synthase or scavenging peroxynitrite reduced SMC death; endothelial denudation or inhibiting gap junctions increased SMC death; delocalization of cytochrome C activated caspases 9 and 3 to induce apoptosis. Vascular cells develop resilience to H2 O2 during ageing by preventing Ca2+ overload and endothelial integrity promotes SMC survival. ABSTRACT:Advanced age is associated with elevated oxidative stress and can protect the endothelium from cell death induced by H2 O2 . Whether such protection occurs for intact vessels or differs between smooth muscle cell (SMC) and endothelial cell (EC) layers is unknown. We tested the hypothesis that ageing protects SMCs and ECs during acute exposure to H2 O2 (200 µm, 50 min). Mouse superior epigastric arteries (SEAs; diameter, ?150 µm) were isolated and pressurized to 100 cmH2 O at 37?C. For SEAs from young (4 months) mice, H2 O2 killed 57% of SMCs and 11% of ECs in males vs. 8% and 2%, respectively, in females. Therefore, SEAs from males were studied to resolve the effect of ageing and experimental interventions. For old (24 months) mice, SMC death was reduced to 10% with diminished accumulation of [Ca2+ ]i in the vessel wall during H2 O2 exposure. In young mice, genetic deletion of IL-10 mimicked the protective effect of ageing on cell death and [Ca2+ ]i accumulation. Whereas endothelial denudation or gap junction inhibition (carbenoxolone; 100 µm) increased SMC death, inhibiting NO synthase (l-NAME, 100 µm) or scavenging peroxynitrite (FeTPPS, 5 µm) reduced SMC death along with [Ca2+ ]i . Despite NO toxicity via peroxynitrite formation, endothelial integrity protects SMCs. Caspase inhibition (Z-VAD-FMK, 50 µm) attenuated cell death with immunostaining for annexin V, cytochrome C, and caspases 3 and 9 pointing to induction of intrinsic apoptosis during H2 O2 exposure. We conclude that advanced age reduces Ca2+ influx that triggers apoptosis, thereby promoting resilience of the vascular wall during oxidative stress.

Dataset Information

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

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

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

Similar Datasets

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