Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications

Abstract

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.

Figure 1. Secondary and tertiary structures of XOR

A, secondary structure of molybdoenzymes XOR, AO, and SO. Arrows designate trypsin sites (Lys186, Lys552) (Amaya et al. 1990). Stars designate cysteine residues modified in reversible XOR conversion (Cys535, Cys992) (Nishino & Nishino, 1997). B, XOR subunit domains, their sizes, and their associated cofactors (Enroth et al. 2000). C, crystal structure of bovine XOR homodimer (Enroth et al. 2000). Copyright 2000 National Academy of Sciences, USA.

Figure 2. The purine degradation pathway

Reprinted from Mathews & Van Holde (1996) with permission of Pearson Education Inc.

Figure 3. Mechanism of XOR reaction with xanthine

A, reductive half-reaction. B, oxidative half-reaction.

Figure 4. Ischaemia–reperfusion injury hypothesis

Derived from Granger et al. (1981) and McCord (1985).

Figure 5. XOR is up-regulated in heart failure

A, XOR immunoblot of myocardial extracts from patients with idiopathic dilated cardiomyopathy (CM) or normal cardiac function (NL) probed with monoclonal anti-XDH antibody. Bands correspond to XDH (145 kDa) and XO (125, 85 kDa). B, densitometry depicting average XOR signal from all patients. Signal is increased 60% in patients with idiopathic dilated cardiomyopathy (*P < 0.05, Student's unpaired t test). From Cappola et al. 2001). Reprinted with permission from Lippincott Williams & Wilkins.