[Frontiers in Bioscience 14, 237-262, January 1, 2009]

Role of xanthine oxidoreductase in cardiac nitroso-redox imbalance

Konstantinos Tziomalos, Joshua M. Hare

Interdisciplinary Stem Cell Institute and Division of Cardiology, Leonard M. Miller School of Medicine, University of Miami

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. XOR - biochemistry and function
4. XOR is upregulated in HF
5. Effects of XOR in myocardial contractility
5.1. Ex vivo studies
5.2. In vivo studies
5.3. Mechanisms involved in the negative inotropic action of XOR
5.3.1. Myocardial energetics
5.3.2. Ca2+ cycling
5.3.3. Structural changes in the myofilaments
6. Cardiac remodeling - the role of XOR
6.1. Hypertrophy
6.2. Apoptosis
6.3. Alterations in matrix structure
7. Ischemic cardiomyopathy - the role of XOR
8. Diastolic dysfunction and XOR
9. Interaction of XOR with other sources of ROS in HF
10. Interaction of XOR with antioxidant systems in HF
11. Cross-talk of oxidative and nitrosative pathways in HF - the role of XOR
12. Peripheral effects of XOR inhibition in HF
13. XOR and adipogenesis
14. Clinical studies of XOR inhibition in HF
15. Perspective
16. Acknowledgements
17. References

1. ABSTRACT

Emerging evidence supports the importance of nitroso-redox balance in the cardiovascular system. Xanthine oxidoreductase (XOR) is a major oxidative enzyme and increased XOR activity, leading to both increased production of reactive oxygen species and uric acid, is implicated in heart failure. Within the heart, XOR activity stimulates cardiomyocyte hypertrophy, apoptosis, and impairs matrix structure. The underpinnings of these derangements can be linked not solely to oxidative stress, but may also involve the process of nitroso-redox imbalance. In this regard, XOR interacts with nitric oxide signaling at numerous levels, including a direct protein-protein interaction with neuronal nitric oxide synthase (NOS1) in the sarcoplasmic reticulum. Deficiency or translocation of NOS1 away from this microdomain leads to increased activity of XOR, which in turn impairs excitation-contraction coupling and myofilament calcium sensitivity. There is a mounting abundance of preclinical data supporting beneficial effects of inhibiting XOR, but translation to the clinic continues to be incomplete. A growing understanding of XOR and its role in nitroso-redox imbalance has great potential to lead to improved pathophysiologic insights and possibly therapeutic advances.