Xanthine Oxidoreductase Is Involved in Macrophage Foam Cell Formation and Atherosclerosis Development

Abstract

Objective-Hyperuricemia is common in patients with metabolic syndrome. We investigated the role of xanthine oxidoreductase (XOR) in atherosclerosis development, and the effects of the XOR inhibitor allopurinol on this process. Methods and Results-Oral administration of allopurinol to ApoE knockout mice markedly ameliorated lipid accumulation and calcification in the aorta and aortic root. In addition, allopurinol treatment or siRNA-mediated gene knockdown of XOR suppressed transformation of J774.1 murine macrophage cells, treated with acetylated LDL or very low density lipoprotein (VLDL) into foam cells. This inhibitory effect of allopurinol was also observed in primary cultured human macrophages. In contrast, overexpression of XOR promoted transformation of J774.1 cells into foam cells. Interestingly, SR-A1, SR-B1, SR-B II, and VLDL receptors in J774.1 cells were reduced by XOR knockdown, and increased by XOR overexpression. Conversely, expressions of ABCA1 and ABCG1 were increased by XOR knockdown and suppressed by XOR overexpression. Finally, productions of inflammatory cytokines accompanied by foam cell formation were also reduced by allopurinol administration. Conclusion-These results strongly suggest XOR activity and/or its expression level to contribute to macrophage foam cell formation. Thus, XOR inhibitors may be useful for preventing atherosclerosis. Key Words: atherosclerosis Ⅲ cell physiology Ⅲ cytokines Ⅲ macrophages Ⅲ xanthine oxidoreductase A relationship between serum uric acid levels and atherosclerotic disease development has been suggested. [1][2][3] In addition, there is epidemiological evidence of an association between hyperuricemia and metabolic syndrome, 1 type 2 diabetes, 4 chronic kidney diseases, 5,6 heart failure incidence in older adults, 7 and with mortality in patients undergoing percutaneous coronary intervention or with acute myocardial infarction. 8 -10 Uric acid itself reportedly functions as an antioxidant, 11 though the process of uric acid synthesis is accompanied by the generation of reactive oxygen species.Xanthine oxidoreductase (XOR) is a key enzyme in the uric acid production pathway; XOR oxidizes hypoxanthine from nucleic acid metabolites into xanthine, and xanthine into uric acid. XOR basically oxidizes a variety of purines and pterins, classified as molybdenum iron-sulfur flavin hydroxylases. XOR tissue and cellular distributions are high in the mammalian liver and intestine due to XOR-rich parenchymal cells. 12 XOR activity is low in human serum, brain, heart, and skeletal muscle, though a recent study revealed microvascular endothelial cells to be rich in XOR activity. 13 It seems that XOR does not induce harmful reactive oxygen species production under normal conditions but in pathological states such as ischemic congestive heart failure, XOR activity increases drastically and XOR localizes within CD68 positive macrophages. 14 Allopurinol, a xanthine oxidase (XO) inhibitor, has been widely used for hyperuricemia treatment. Oxypurinol, a hydroxide and the main met...

Linking uric acid metabolism to diabetic complications

“…Moreover, high SUA levels were shown to predict MetS in a Japanese cohort [35] . We previously reported an association between inflammation, macrophage activation, and SUA production via XDH/XO activation in an animal model [36] . In summary, a link between SUA and insulin resistance has repeatedly been shown, and UA itself reportedly plays an important role in the exacerbation of insulin resistance [37] .…”

Serum uric acid and its association with hypertension, early nephropathy and chronic kidney disease in type 2 diabetic patients

“…Oxidoreductase activity also contributes to macrophage foam cell formation and inflammation and macrophage activation is thought to be involved in the pathogenesis of DN. 34 MA is a marker of endothelial dysfunction and associated with an increased risk of cardiovascular morbidity in patients with diabetes. 35 In the present study, we have evaluated the relationships between UA concentration and degree of urinary albumin excretion.…”

Vascular Calcification in Type 2 Diabetes: A Role for Allopurinol?

“…The high levels of xanthine oxidase in subjects with type 2 DM may reflect the increased oxidant activity, on the background of chronic hyperglycaemia. 10 Recently, it has been demonstrated in experimental models that xanthine oxidase plays a key role in transformation of macrophages into foam cells and thus promote the processes of atherosclerosis and VC [43].…”

“…Increased xanthine oxidase and uric acid expression has been co-localized with lipid particles in atherosclerotic plaque samples [90], which may be circumstantial evidence of their involvement in the processes of calcification. The recent demonstration of the role of xanthine oxidase in the transformation of macrophages into foam cells and development of atherosclerosis, in experimental models [43], opens other plausible avenues for the therapeutic uses of Allopurinol in this setting.…”