Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications.
There is substantial evidence that oxidative stress participates in the pathophysiology of cardiovascular disease. Biochemical, molecular and pharmacological studies further implicate xanthine oxidoreductase (XOR) as a source of reactive oxygen species in the cardiovascular system. XOR is a member of the molybdoenzyme family and is best known for its catalytic role in purine degradation, metabolizing hypoxanthine and xanthine to uric acid with concomitant generation of superoxide. Gene expression of XOR is regulated by oxygen tension, cytokines and glucocorticoids. XOR requires molybdopterin, iron-sulphur centres, and FAD as cofactors and has two interconvertible forms, xanthine oxidase and xanthine dehydrogenase, which transfer electrons from xanthine to oxygen and NAD(+), respectively, yielding superoxide, hydrogen peroxide and NADH. Additionally, XOR can generate superoxide via NADH oxidase activity and can produce nitric oxide via nitrate and nitrite reductase activities. While a role for XOR beyond purine metabolism was first suggested in ischaemia-reperfusion injury, there is growing awareness that it also participates in endothelial dysfunction, hypertension and heart failure. Importantly, the XOR inhibitors allopurinol and oxypurinol attenuate dysfunction caused by XOR in these disease states. Attention to the broader range of XOR bioactivity in the cardiovascular system has prompted initiation of several randomised clinical outcome trials, particularly for congestive heart failure. Here we review XOR gene structure and regulation, protein structure, enzymology, tissue distribution and pathophysiological role in cardiovascular disease with an emphasis on heart failure.
Berry
Cristine E
CE
The Johns Hopkins Hospital School of Medicine, Cardiology Division, 600 N Wolfe Street, Carnegie 568, Baltimore, MD 21287, USA.
Hare
Joshua M
JM
D000818:Animals; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000503:physiopathology*; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014018:Tissue Distribution; D014968:Xanthine Dehydrogenase / Q000378:metabolism; D014969:Xanthine Oxidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase