Xanthine oxidase inhibition protects against Western diet-induced aortic stiffness and impaired vasorelaxation in female mice.
Xanthine oxidase inhibition protects against Western diet-induced aortic stiffness and impaired vasorelaxation in female mice.
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DOI：
10.1152/ajpregu.00483.2016
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发表时间：
2017-08
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通讯作者：
G. Lastra;C. Manrique;Guanghong Jia;A. Aroor;M. Hayden;Brady J Barron;B. Niles;J. Padilla;J. Sowers
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文献类型：
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作者：
G. Lastra;C. Manrique;Guanghong Jia;A. Aroor;M. Hayden;Brady J Barron;B. Niles;J. Padilla;J. Sowers
高脂肪、高果糖饮食[西方饮食（WD）]的消费促进血管僵硬，这是心血管疾病（CVD）发展的关键因素。肥胖和糖尿病女性表现出比男性更大的动脉硬度，这有助于这些女性CVD的发病率增加。此外，高果糖饮食通过黄嘌呤氧化酶（XO）激活导致尿酸血浆浓度升高，尿酸升高也与血管僵硬度增加有关。然而，黄嘌呤氧化酶活性增加和尿酸导致肥胖女性血管僵硬的机制仍有待完全揭示。因此，我们研究了XO抑制对雌性C57 BL/6 J小鼠内皮功能和血管硬度的影响，这些小鼠喂食WD或常规食物16周。原子力显微镜观察显示，WD喂养可导致主动脉僵硬度增加（16.19 ± 1.72 kPa vs.5.21 ± 0.54 kPa，P < 0.05），同时也导致异常的主动脉内皮依赖性和非依赖性血管舒张。用别嘌呤醇（广泛用于临床环境）抑制XO显著改善血管松弛和减弱僵硬（16.9 ± 0.50 vs. 3.44 ± 0.50 kPa，P < 0.05），同时降低血清尿酸水平（0.55 ± 0.98 vs. 0.21 ± 0.04 mg/dL，P < 0.05）。此外，通过免疫组织化学和透射电子显微镜分析，别嘌呤醇改善了WD诱导的主动脉组织纤维化和氧化应激标志物。总的来说，这些结果表明，XO抑制对WD诱导的血管氧化应激，纤维化，血管舒张受损，和主动脉僵硬的女性。此外，XO激活导致的过度氧化应激似乎在介导女性长期暴露于WD消耗诱导的血管功能障碍中起关键作用。
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.