Xanthine oxidase inhibition protects against Western diet-induced aortic stiffness and impaired vasorelaxation in female mice

Am J Physiol Regul Integr Comp Physiol. 2017 Aug 1;313(2):R67-R77. doi: 10.1152/ajpregu.00483.2016. Epub 2017 May 24.

Abstract

Consumption of a high-fat, high-fructose diet [Western diet (WD)] promotes vascular stiffness, a critical factor in the development of cardiovascular disease (CVD). Obese and diabetic women exhibit greater arterial stiffness than men, which contributes to the increased incidence of CVD in these women. Furthermore, high-fructose diets result in elevated plasma concentrations of uric acid via xanthine oxidase (XO) activation, and uric acid elevation is also associated with increased vascular stiffness. However, the mechanisms by which increased xanthine oxidase activity and uric acid contribute to vascular stiffness in obese females remain to be fully uncovered. Accordingly, we examined the impact of XO inhibition on endothelial function and vascular stiffness in female C57BL/6J mice fed a WD or regular chow for 16 wk. WD feeding resulted in increased arterial stiffness, measured by atomic force microscopy in aortic explants (16.19 ± 1.72 vs. 5.21 ± 0.54 kPa, P < 0.05), as well as abnormal aortic endothelium-dependent and -independent vasorelaxation. XO inhibition with allopurinol (widely utilized in the clinical setting) substantially improved vascular relaxation and attenuated stiffness (16.9 ± 0.50 vs. 3.44 ± 0.50 kPa, P < 0.05) while simultaneously lowering serum uric acid levels (0.55 ± 0.98 vs. 0.21 ± 0.04 mg/dL, P < 0.05). In addition, allopurinol improved WD-induced markers of fibrosis and oxidative stress in aortic tissue, as analyzed by immunohistochemistry and transmission electronic microscopy. Collectively, these results demonstrate that XO inhibition protects against WD-induced vascular oxidative stress, fibrosis, impaired vasorelaxation, and aortic stiffness in females. Furthermore, excessive oxidative stress resulting from XO activation appears to play a key role in mediating vascular dysfunction induced by chronic exposure to WD consumption in females.

Keywords: Western diet; allopurinol; females; oxidative stress; vascular stiffness.

MeSH terms

  • Allopurinol / administration & dosage*
  • Animals
  • Aorta / drug effects
  • Aorta / physiology*
  • Diet, Western*
  • Enzyme Inhibitors / administration & dosage
  • Female
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Uric Acid / blood*
  • Vascular Stiffness / drug effects
  • Vascular Stiffness / physiology*
  • Vasodilation / drug effects
  • Vasodilation / physiology*
  • Vasomotor System / drug effects
  • Vasomotor System / physiology
  • Xanthine Oxidase / antagonists & inhibitors
  • Xanthine Oxidase / metabolism*

Substances

  • Enzyme Inhibitors
  • Uric Acid
  • Allopurinol
  • Xanthine Oxidase