Role of xanthine oxidoreductase in cardiac nitroso-redox imbalance.
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.
Tziomalos
Konstantinos
K
Interdisciplinary Stem Cell Institute and Division of Cardiology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
Hare
Joshua M
JM
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D006801:Humans; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D015538:Nitrosation; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D014968:Xanthine Dehydrogenase / Q000378:metabolism*
D000975:Antioxidants; D017382:Reactive Oxygen Species; D014968:Xanthine Dehydrogenase