Xanthine Oxidase Inhibition and Heart Failure

Abstract

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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“…1, 2A & 2B). NADPH oxidase and xanthine oxidase are two important enzymes that play significant role in cardiovascular pathology and these are the major enzymatic source of ROS in cardiovascular system [40], [41]. Increase in the activities of these enzymes leads to increased production of superoxide radicals that ultimately lead to cardiac dysfunction [42].…”

Xanthine Oxidoreductase Depletion Induces Renal Interstitial Fibrosis Through Aberrant Lipid and Purine Accumulation in Renal Tubules

“…Furthermore, lowering uric acid with the use of XOR inhibitor can improve the progression of renal disease, ischemic injuries, inflammatory diseases, and chronic heart failure 34–36 . On the other hand, several large cohort studies showed that hypouricemia as well as hyperuricemia were also associated with cardiovascular disease, stroke and chronic kidney disease in subjects with hypertension or diabetes, in addition to the general population 37–39 .…”

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