Xanthine oxidase inhibition ameliorates cardiovascular dysfunction in dogs with pacing-induced heart failure

Amado, Luciano C.; Saliaris, Anastasios; Raju, Sarath; Lehrke, Stephanie; STJOHN, M; Xie, Jin Sheng; Stewart, Garrick C.; Fitton, Torin P.; Minhas, Khalid M.; Brawn, Jeffrey D.

doi:10.1016/j.yjmcc.2005.04.008

Cited by 69 publications

(52 citation statements)

References 36 publications

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“…It is responsible for the generation of free radicals in the terminal steps in purine metabolism, which have previously been associated with higher vulnerability to developing AF 14. Allopurinol, a selective XO inhibitor, has been demonstrated to reverse structural remodeling in the failing ventricle 47, 48. Allopurinol prevented hyperglycemia‐induced oxidative stress, cardiomyocyte hypertrophy and cardiac fibrosis and attenuated cardiac dysfunction,15 in which prevention of ROS‐induced oxidative stress and reduction of myocardial collagen formation may represent one of the major pathogenic mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Yang

Zhao

Qiu

et al. 2018

JAHA

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BackgroundThere are several mechanisms, including inflammation, oxidative stress and abnormal calcium homeostasis, involved in the pathogenesis of atrial fibrillation. In diabetes mellitus (DM), increased oxidative stress may be attributable to higher xanthine oxidase activity. In this study, we examined the relationship between oxidative stress and atrial electrical and structural remodeling, and calcium handling abnormalities, and the potential beneficial effects of the xanthine oxidase inhibitor allopurinol upon these pathological changes.Methods and ResultsNinety rabbits were randomly and equally divided into 3 groups: control, DM, and allopurinol‐treated DM group. Echocardiographic and hemodynamic assessments were performed in vivo. Serum and tissue markers of oxidative stress and atrial fibrosis, including the protein expression were examined. Atrial interstitial fibrosis was evaluated by Masson trichrome staining. ICaL was measured from isolated left atrial cardiomyocytes using voltage‐clamp techniques. Confocal microscopy was used to detect intracellular calcium transients. The Ca2+ handling protein expression was analyzed by Western blotting. Mitochondrial‐related proteins were analyzed as markers of mitochondrial function. Compared with the control group, rabbits with DM showed left ventricular hypertrophy, increased atrial interstitial fibrosis, oxidative stress and fibrosis markers, ICaL and intracellular calcium transient, and atrial fibrillation inducibility. These abnormalities were alleviated by allopurinol treatment.ConclusionsAllopurinol, via its antioxidant effects, reduces atrial mechanical, structural, ion channel remodeling and mitochondrial synthesis abnormalities induced by DM‐related increases in oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Yang

Zhao

Qiu

et al. 2018

JAHA

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“…With regard to XOR, both protein abundance and enzyme activity are elevated in the failing heart. 57,[107][108][109] The availability of allopurinol and its active metabolite oxypurinol as safe, well-tested drugs for XO inhibition has greatly aided the study of the role of XOR in heart failure. In mouse models of experimental MI, XO inhibition leads to greater survival, improved left ventricular function, and enhanced mechanoenergetic coupling.…”

Section: Xor In Heart Failurementioning

confidence: 99%

Nitroso–Redox Interactions in the Cardiovascular System

2006

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“…24 It is important to note, however, that in all these experimental models of heart failure, the beneficial effects of XO inhibition were achieved because XO activities were increased within the myocardium; treatment with either allopurinol or oxypurinol restored XO activity to baseline levels and myocardial function was restored. 19,21,22,[25][26][27] These findings, therefore, suggest that by limiting oxidant stress to maintain levels of ROS required for ambient signaling, XO inhibition abrogates the destructive effects of ROS on various intracellular mechanisms that maintain function and integrity in the working cardiomyocyte. In addition, it has also been suggested that decreases in uric acid levels seen with XO inhibition have an antiinflammatory effect on the cardiovascular system.…”

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confidence: 92%

“…Unlike cAMPmodulating inotropes, XO inhibition decreases myocardial oxygen consumption, thereby sparing energy expenditure in the energy-deprived failing heart. 22,25 In a more recent study, XO inhibition was also shown to restore high-energy phosphates to basal levels. 26 The mechanisms of action of XO inhibition have not been fully elucidated.…”

mentioning

confidence: 95%

“…These findings corroborate positive results seen in other studies that demonstrated improved contractile parameters in heart failure with XO inhibition. 19,21,22,[25][26][27] The positive inotropy induced by XO inhibition in the setting of heart failure differs significantly from standard clinically used pharmacological inotropes. Unlike cAMPmodulating inotropes, XO inhibition decreases myocardial oxygen consumption, thereby sparing energy expenditure in the energy-deprived failing heart.…”

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confidence: 99%

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Xanthine Oxidase Inhibition and Heart Failure

Hajjar

Leopold

2006

Circulation Research

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M yocardial dysfunction and heart failure perturb cardiovascular homeostatic signaling pathways as well as initiate a program of molecular, biochemical, and structural modifications to remodel the failing ventricle. Accumulating evidence suggests that the cardiovascular redox state plays an integral role in these processes. In fact, in the failing heart, elevated levels of reactive oxygen species (ROS) and cardiomyocyte oxidant stress are associated with maladaptive ventricular remodeling and a progressive decline in cardiovascular function.The association between ROS and heart failure has been established. Increased indices of oxidant stress have been measured in patients with congestive heart failure. In clinical studies, patients with heart failure were found to have evidence of lipid peroxidation and elevated 8-iso-prostaglandin F 2␣ levels 1-4 whereas in experimental models of heart failure, investigators have been able to directly measure increased ROS production from cardiomyocytes. 5,6 These findings have been corroborated in studies that measured ROS levels in explanted human hearts at the time of transplant. 7 Furthermore, a number of neurohormonal and mechanical stressors that are associated with the heart failure phenotype augment ROS generation. 8,9 Prolonged exposure to ROS, in turn, results in cardiomyocyte dysfunction. 10 At a cellular level, elevated levels of ROS impair cardiomyocyte function by damaging ion channels as well as inhibiting contractility. ROS disrupt the structural integrity of ion channels via membrane lipid peroxidation. 2,11 ROS also decrease expression and activity of the sarcoplasmic reticulum Ca 2ϩ ATPase SERCA2, 12 which is critical for effective cardiac calcium handling. Interestingly, ROS have also been shown to decrease myofilament calcium sensitivity by activation of ASK-1, a redox-sensitive kinase. ASK-1 phosphorylates troponin T and thereby decreases contractility and regulates calcium handling. 13 Concomitant with these adverse effects on cardiomyocyte function, ROS stimulates a number of responses associated with the ventricular remodeling processes. These include ROS-mediated activation of matrix metalloproteinases to alter the architecture of the extracellular matrix, 14 modulation of signal transduction pathways that initiate cardiomyocyte hypertrophy, 15 and apoptosis or cell death. 16 Taken together, these observations suggest that one mechanism to halt deleterious ventricular remodeling and abnormal cardiomyocyte functional responses is to decrease oxidant stress by limiting ROS production. ROS are derived from the superoxide anion, a one-electron reduction product of oxygen. In the myocardium, superoxide anion may be generated by both metabolic and enzymatic sources including mitochondrial respiration, xanthine oxidase (XO), NAD(P)H oxidases, and, when substrate or cofactors are not replete, uncoupled nitric oxide synthase(s). 17,18 In the failing heart, activation of these ROS-generating systems leads to the accumulation of superoxide anions and the formati...

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Xanthine oxidase inhibition ameliorates cardiovascular dysfunction in dogs with pacing-induced heart failure

Cited by 69 publications

References 36 publications

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Nitroso–Redox Interactions in the Cardiovascular System

Xanthine Oxidase Inhibition and Heart Failure

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