P704Obesity and insulin resistance are not associated with endothelial dysfunction in rat aortas

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Background and aims: Obesity and insulin resistance (OIR) are usually associated with endothelial dysfunction. Although endothelial dysfunction has been shown to be an early, reversible precursor of ischaemic heart disease, the underlying mechanisms are not fully elucidated. Methods: In this study, OIR was induced in rats by a 16-week high sucrose, high fat diet (HSFD) regimen. We assessed the vascular effects of OIR on aortic contraction/relaxation by means of ex vivo isometric tension studies, and the expression of critical vascular proteins was investigated by western blot analyses. Results: Biometric data confirmed obesity in terms of total body mass (OIR group: 442±2 g vs Lean group: 354±3g; p<0.05) and visceral fat mass (OIR: 23±1 g vs Lean: 11±1 g; p<0.05). Fasting glucose levels were significantly elevated in OIR animals (OIR: 7.4±0.4 mmol/L vs Lean: 5.8±0.5 mmol/L; p<0.05). There were no differences observed in the cumulative phenylephrine-induced contractile responses of lean and OIR aortic rings without perivascular adipose tissue (PVAT), and this trend was not affected by the presence of PVAT. PVAT exerted significant anti-contractile effects in OIR rings compared to PVAT-free OIR rings, which was abolished by removal of the endothelium (Area Under the Curve in OIR-PVAT+Endothelium: 86.0 vs OIR+PVAT+Endothelium: 64.3 vs OIR+PVAT-Endothelium: 110.4; p<0.05). PVAT-free OIR rings showed significantly greater % maximum acetylcholine (ACh)-induced relaxation (OIR: 94.5±6% vs Lean: 70.4±3.2%; p<0.005). This trend was maintained in rings with PVAT. In PVAT-free aortic tissue, OIR was associated with reduced eNOS levels (Lean: 100% vs OIR: 31.6±2%; p<0.05), and unchanged total PKB/Akt levels. Interestingly, OIR aortic tissue expressed reduced p22-phox (Lean: 100% vs OIR: 53.4±0.8%; p<0.05) and nitrotyrosine (Lean: 100% vs OIR: 41.7±11%; p<0.05) levels respectively. Conclusion: In our hands, diet-induced OIR seemed to be associated with significant pro-relaxation effects in PVAT-free aortic rings, despite significantly reduced eNOS levels. The relaxation was unaffected by the presence of PVAT. Although there were no differences in the lean vs. OIR contractile responses, the presence of PVAT did exert endothelium-dependent anti-contractile responses in OIR aortic rings. In view of the above functional data and associated reduced cellular oxidative stress markers, the findings suggest that in our hands OIR did not induce endothelial dysfunction in the aortas, but rather an adaptive response.