Pathophysiology of circulating xanthine oxidoreductase: new emerging roles for a multi-tasking enzyme.

Abstract The enzyme xanthine oxidoreductase (XOR) catalyses the last step of purine degradation in the highest uricotelic primates as a rate-limiting enzyme in nucleic acid catabolism. Although XOR has been studied for more than a century, this enzyme continues to arouse interest because its involvement in many pathological conditions is not completely known. XOR is highly evolutionarily conserved; moreover, its activity is very versatile and tuneable at multiple-levels and generates both oxidant and anti-oxidant products. This review covers the basic information on XOR biology that is essential to understand its enzymatic role in human pathophysiology and provides a comprehensive catalogue of the experimental and human pathologies associated with increased serum XOR levels. The production of radical species by XOR oxidase activity has been intensively studied and evaluated in recent decades in conjunction with the cytotoxic consequences and tissue injuries of various pathological conditions. More recently, a role has emerged for the activity of endothelium-bound enzymes in inducing the vascular response to oxidative stress, which includes the regulation of pro-inflammatory and pro-thrombotic activities of endothelial cells. The possible physiological functions of circulating XOR and the products of its enzyme activity are presented here together with their implications in cardiovascular and metabolic diseases

An investigation of the potential influence of serum uric acid concentration on regulation of the human cardiovascular system

Background There are strong epidemiological associations between high serum uric acid concentrations and increased cardiovascular risk. However, it is unclear if uric acid is an independent causal risk factor, serves a protective role due to its antioxidant properties, or simply acts as a passive marker of risk through association with other factors. The distinction is important because, if acting as a causal risk factor, treatment to lower uric acid concentrations might reduce cardiovascular risk.Aims: To study the cardiovascular effects of raising and lowering circulating uric acid concentrations, so as to identify potential mechanisms by which uric acid could impair cardiovascular function or, as an antioxidant, serve a protective role.Methods: I developed a technique of uric acid administration that allowed the effects of raised concentrations to be examined in vivo. The potential impact on serum antioxidant capacity, plasma viscosity, platelet aggregability, systemic haemodynamics, baroreflex sensitivity, large arterial stiffness, and endothelial function were studied in healthy subjects. The effects of high uric acid concentrations were studied in a model of acute exercise-induced oxidative stress, and in regular smokers and patients with type 1 diabetes who are ordinarily exposed to chronic oxidative stress. The effects of lowering uric acid, by means of urate oxidase, were studied in patients with type 2 diabetes to explore whether this might improve vascular function in these patients.Results: Raising and lowering uric acid concentrations had no effect on vascular function in healthy subjects. Uric acid administration significantly increased serum antioxidant capacity, reduced oxidative stress during acute aerobic exercise, and improved endothelium-dependent vascular responses in regular smokers and patients with type 1 diabetes. Lowering uric acid concentrations did not influence vascular function in healthy subjects or patients with type 2 diabetes.Conclusions: High uric acid concentrations did not impair vascular function, at least in the acute situation, and appear to preserve vascular function by protecting against oxidative stress in smokers and patients with type 1 diabetes. These findings do not support a causal link between high serum uric acid concentrations and increased cardiovascular risk. Further research is required to define the mechanisms by which high uric acid concentrations ameliorate endothelial dysfunction, and to examine whether these properties have therapeutic potential in diseases characterised by oxidative stress