Endothelial dysfunction in insulin-resistant rats is associated with oxidative stress and COX pathway dysregulation.
Because insulin resistance is inevitably associated with cardiovascular complications, there is a need to further investigate the potential involvement of oxidative stress and the cyclo-oxygenase (COX) pathway in the vascular modifications associated to this pathological context. Endothelial function was evaluated in control and fructose-fed rats (FFR) by i) in vitro study of endothelium-dependent and -independent relaxations of aortic rings, and ii) in vivo telemetric evaluation of pressor response to norepinephrine. After 9 weeks of diet, FFR displayed hypertriglyceridemia, hyperinsulinemia and exaggerated response to glucose overload. Aortic rings from control rats and FFR exhibited comparable endothelium-dependent relaxations to Ach. In the presence of indomethacin, relaxations were significantly reduced. FFR showed exaggerated pressor responses to norepinephrine that were abolished with indomethacin. Urinary nitrites/nitrates, 8-isoprostanes and thromboxane B2 excretion levels were markedly enhanced in FFR, whereas the plasma levels of 6-keto prostaglandin F1alpha were unchanged. In conclusion, fructose overload in rats induced hypertriglyceridemia and insulin resistance associated with an enhanced oxidative stress. This was associated with COX pathway dysregulation which could be one of the contributors to subsequent vascular dysfunction. Consequently, reduction of oxidative stress and regulation of the COX pathway could represent new potential therapeutic strategies to limit vascular dysfunction and subsequent cardiovascular complications associated with insulin resistance.
Oudot
A
A
Pelvipharm, Orsay, France.
Behr-Roussel
D
D
Compagnie
S
S
Caisey
S
S
Le Coz
O
O
Gorny
D
D
Alexandre
L
L
Giuliano
F
F
D000818:Animals; D004730:Endothelium, Vascular / Q000502:physiology*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D007328:Insulin; D014662:Vasoconstrictor Agents; D011451:Prostaglandin-Endoperoxide Synthases; D009638:Norepinephrine