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Xanthine Oxidase Inhibition Decreases Vascular Stiffness in Western Diet Fed Male and Female Mice
Author(s) -
Aroor Annayya,
Habibi Javad,
Jia Guanghong,
Manrique Camila,
Sun Zhe,
MartinezLemus Luis,
Meininger Gerald,
Sowers James
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1276.9
Subject(s) - allopurinol , endocrinology , xanthine oxidase , medicine , uric acid , arterial stiffness , endothelial dysfunction , oxidative stress , xanthine , vascular smooth muscle , nadph oxidase , febuxostat , chemistry , hyperuricemia , biochemistry , blood pressure , smooth muscle , enzyme
Endothelial and arterial stiffness play a central role in the development and progression of cardiovascular disease. Obesity and diabetes are associated with development of premature arterial stiffness. We have recently reported that male and female mice fed a diet high in fat and refined carbohydrates including fructose (western diet – WD) develop premature cardiac and vascular stiffness. In this regard, excess uric acid formed from excess fructose ingestion is emerging as a risk factor for vascular stiffness and vascular injury. We hypothesized that increased tissue xanthine oxidase activity and increased hepatic production of uric acid is associated with increased vascular stiffness and vascular dysfunction in WD fed males and females. Four week‐old C57BL6/J male and female mice were fed a WD with excess fat (46%) and fructose (17.5%) for 16 weeks with or without access to allopurinol in the drinking water (125mg/L), a potent xanthine oxidase inhibitor. Plasma uric acid levels were increased in plasma from WD male and female mice and these levels were normalized by allopurinol. Endothelial stiffness as determined by atomic force microscopy, was significantly increased in WD fed mice and this was significantly decreased by allopurinol administration. Increased endothelial stiffness was associated with increased fibrosis and vascular oxidative stress as determined by 3‐nitrotyrosine staining and this was prevented by allopurinol. Allopurinol treatment significantly attenuated WD induced increases in xanthine oxidase activity in aorta. Allopurinol also improved WD induced impairment of endothelial mediated vascular relaxation. WD feeding was associated with increased macrophage inflammatory response (M1 polarization) in aorta that was ameliorated by allopurinol. Taken together, these findings support that increased production of uric acid and enhanced xanthine oxidase activity in aorta promote vascular oxidative stress, macrophage inflammatory responses and vascular fibrosis/stiffness. We posit that increased cardiovascular xanthine oxidase activity associated with consumption of a WD plays a central role in the increased oxidative stress, inflammation and fibrosis. Support or Funding Information NIH R01 HL107910‐01 for J.R.S and the Veterans Affairs Merit System (Grant 0018) for J.R.S