Xanthine oxidase inhibitors improve energetics and function after infarction in failing mouse hearts

Naumova, Anna V.; Chacko, V. P.; Ouwerkerk, Ronald; Stull, Linda B.; Marbán, Eduardo; Weiss, Robert G.

doi:10.1152/ajpheart.00831.2005

Cited by 64 publications

(62 citation statements)

References 47 publications

(78 reference statements)

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“…One group was untreated, the second one was treated with the general antioxidant N-acetylcysteine (NAC; 10 g/l in the drinking water), and the third group was treated with oxypurinol (OXY; an inhibitor of XO, 1 mM in the drinking water) until day 12. The concentration of oxypurinol was previously shown to inhibit XO (35). Fresh solutions were made every 48 h. On day 12, all mice were euthanized, blood was collected, and gastrocnemius muscles were removed and frozen in liquid nitrogen.…”

Section: Animalsmentioning

confidence: 99%

Inhibition of xanthine oxidase reduces hyperglycemia-induced oxidative stress and improves mitochondrial alterations in skeletal muscle of diabetic mice

Bravard

Bonnard

Durand

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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Bravard A, Bonnard C, Durand A, Chauvin M, Favier R, Vidal H, Rieusset J. Inhibition of xanthine oxidase reduces hyperglycemia-induced oxidative stress and improves mitochondrial alterations in skeletal muscle of diabetic mice. Am J Physiol Endocrinol Metab 300: E581-E591, 2011. First published January 11, 2011; doi:10.1152/ajpendo.00455.2010.-Reactive oxygen species (ROS) have been widely implicated in the pathogenesis of diabetes and more recently in mitochondrial alterations in skeletal muscle of diabetic mice. However, so far the exact sources of ROS in skeletal muscle have remained elusive. Aiming at better understanding the causes of mitochondrial alterations in diabetic muscle, we designed this study to characterize the sites of ROS production in skeletal muscle of streptozotocin (STZ)-induced diabetic mice. Hyperglycemic STZ mice showed increased markers of systemic and muscular oxidative stress, as evidenced by increased circulating H2O2 and muscle carbonylated protein levels. Interestingly, insulin treatment reduced hyperglycemia and improved systemic and muscular oxidative stress in STZ mice. We demonstrated that increased oxidative stress in muscle of STZ mice is associated with an increase of xanthine oxidase (XO) expression and activity and is mediated by an induction of H2O2 production by both mitochondria and XO. Finally, treatment of STZ mice, as well as high-fat and high-sucrose diet-fed mice, with oxypurinol reduced markers of systemic and muscular oxidative stress and prevented structural and functional mitochondrial alterations, confirming the in vivo relevance of XO in ROS production in diabetic mice. These data indicate that mitochondria and XO are the major sources of hyperglycemia-induced ROS production in skeletal muscle and that the inhibition of XO reduces oxidative stress and improves mitochondrial alterations in diabetic muscle.

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Section: Animalsmentioning

confidence: 99%

Inhibition of xanthine oxidase reduces hyperglycemia-induced oxidative stress and improves mitochondrial alterations in skeletal muscle of diabetic mice

Bravard

Bonnard

Durand

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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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: 91%

“…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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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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“…The first is phenotyping of genetically modified mice and their wildtype controls (6 -9). The second application is characterizing the diseased heart (10 -14), sometimes combined with a study of the effects of a particular intervention (15)(16)(17)(18)(19)(20)(21). To validate the values of the MRI-based global functional parameters, several authors compare their findings with ex vivo measurements of the weight of the mouse heart (22) or to other volume measurements using, eg, positron emission tomography (23) as well as the conductance microcatheter technique (24).…”

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confidence: 99%

Evaluation of manual and automatic segmentation of the mouse heart from CINE MR images

Heijman

Aben²,

Penners³

et al. 2007

Magnetic Resonance Imaging

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Purpose:To compare global functional parameters determined from a stack of cinematographic MR images of mouse heart by a manual segmentation and an automatic segmentation algorithm. Materials and Methods:The manual and automatic segmentation results of 22 mouse hearts were compared. The automatic segmentation was based on propagation of a minimum cost algorithm in polar space starting from manually drawn contours in one heart phase. Intra-and interobserver variability as well as validity of the automatic segmentation was determined. To test the reproducibility of the algorithm the variability was calculated from the intraand interobserver input. Results:The mean time of segmentation for one dataset was around 10 minutes and Ϸ2.5 hours for automatic and manual segmentation, respectively. There were no significant differences between the automatic and the manual segmentation except for the end systolic epicardial volume. The automatically derived volumes correlated well with the manually derived volumes (R 2 ϭ 0.90); left ventricular mass with and without papillary muscle showed a correlation R 2 of 0.74 and 0.76, respectively. The manual intraobserver variability was superior to the interobserver variability and the variability of the automatic segmentation, while the manual interobserver variability was comparable to the variability of the automatic segmentation. The automatic segmentation algorithm reduced the bias of the intra-and interobserver variability. Conclusion:We conclude that automatic segmentation of the mouse heart provides a fast and valid alternative to manual segmentation of the mouse heart.

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Xanthine oxidase inhibitors improve energetics and function after infarction in failing mouse hearts

Cited by 64 publications

References 47 publications

Inhibition of xanthine oxidase reduces hyperglycemia-induced oxidative stress and improves mitochondrial alterations in skeletal muscle of diabetic mice

Inhibition of xanthine oxidase reduces hyperglycemia-induced oxidative stress and improves mitochondrial alterations in skeletal muscle of diabetic mice

Xanthine Oxidase Inhibition and Heart Failure

Evaluation of manual and automatic segmentation of the mouse heart from CINE MR images

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