Are either or both hyperuricemia and xanthine oxidase directly toxic to the vasculature? A critical appraisal

Abstract

Basic research and clinical studies have implicated a role for hyperuricemia and for xanthine oxidoreductase (XOR), the enzyme that generates uric acid (UA), in not only gout but also vascular diseases. At present, asymptomatic hyperuricemia (i.e., in the absence of gout, urate nephrolithiasis, or tumor lysis syndrome) is not an indication for therapy. With the rise over the past several decades in prevalence of both gout and hyperuricemia, clarifying the potential adverse effects of hyperuricemia (in patients with and without gout) is of public health importance. UA is not simply an inert end-product of purine metabolism in humans, but rather has potential antioxidant, pro-oxidant, and pro-inflammatory effects. However controversy remains as to which, if any, of these effects are of clinical relevance in development and complications of human vascular diseases in gout and asymptomatic hyperuricemia. Clearly, not all individuals with hyperuricemia develop gout, and studies to date have also been unable to clarify in which subjects hyperuricemia may have detrimental effects on the vasculature. Further, studies of urate-lowering therapy with XOR inhibition or uricosuric agents have not been able to definitively identify whether any such effects may be mediated by UA versus XO. Adequately sized, prospective randomized clinical trials of sufficient duration, and employing appropriate biomarkers, now appear critical to resolve the putative toxic roles of UA and XO in the human arterial circulation.

Figures

Figure 1

Uric acid (UA) is not an inert endproduct of purine catabolism, and interacts with other molecules in alternative pathways of degradation that can modulate oxidative stress, as illustrated here and discussed in the text. Abbreviations: ONOO− = peroxynitrite O2− = superoxide anion MPO = myeloperoxidase NO = nitric oxide H2O2 = hydrogen peroxide TRP = transthyretin-related protein

Figure 2

Model for UA and XO interactions with vascular cells that affect oxidative stress and vascular pathophysiology (see also text and Table 1). In this model, UA turns on “inflammatory”, cytotoxic, and dysfunctional responses, including up-regulation of the renin-angiotensin system in cultured ECs, and arterial SMC proliferation and migration. These effects are mediated by UA-induced oxidative stress in ECs, scavenging of NO and induction of EC arginase that reduces production of vasodilatory NO. There are additional adverse consequences for cell redox status and NO levels of oxidative degradation of UA (in the presence of peroxide) by neutrophil-derived MPO. Soluble UA-induced promotion of NO degradation by oxidation and effects on arginase expression are illustrated, as are adverse effects of peroxynitrite whose oxidant effects are inhibited by UA. In this model, XO expression is increased in macrophages, and on EC surfaces by inflammatory conditions (e.g., gouty arthritis) and ischemia. Moreover, XO promotes oxidative stress in ECs, and impairs endothelial function independent of UA generation. XO and UA also stimulate macrophage-mediated inflammation in the artery wall. Not depicted here, but discussed in the text, are potential effects of XOR inhibition on accumulation of upstream precursors such as inosine and adenosine that have anti-inflammatory properties. Abbreviations: ONOO− = peroxynitrite O2− = superoxide anion MPO = myeloperoxidase NO = nitric oxide H2O2 = hydrogen peroxide GI = gastrointestinal XDH = xanthine dehydrogenase XO = xanthine oxidase PPARγ = peroxisome proliferator-activated receptor gamma HIF-1α = hypoxia inducible factor alpha EC = endothelial cell SMC = smooth muscle cell eNOS = endothelial nitric oxide synthase

Figure 3

Schematic of currently available clinical evidence-base from which inferences regarding vascular effects of UA (and XO) have been made. The schematic summarizes key needs and appropriate design considerations for future studies to enable truly definitive clinical evaluation of the role of UA and/or XO in vascular disease.