Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the heart ischaemic conditions induce metabolic changes known to have profound effects on Ca(2+) signalling during excitation-contraction coupling. Ischaemia also affects the redox state of the cell. However, the role of cytosolic redox couples, such as the NADH/NAD(+) redox system, for the regulation of Ca(2+) homeostasis has remained elusive. We studied the effects of NADH and NAD(+) on sarcoplasmic reticulum (SR) Ca(2+) release in permeabilized rat ventricular myocytes as well as on Ca(2+) uptake by SR microsomes and ryanodine receptor (RyR) single channel activity. Exposure of permeabilized myocytes to NADH (2 mm; [Ca(2+)](cyt)= 100nm) decreased the frequency and the amplitude of spontaneous Ca(2+) sparks by 62% and 24%, respectively. This inhibitory effect was reversed by NAD(+) (2 mm) and did not depend on mitochondrial function. The inhibition of Ca(2+) sparks by NADH was associated with a 52% decrease in SR Ca(2+) load. Some of the effects observed with NADH may involve the generation of superoxide anion (O(2)(-).) as they were attenuated to just a transient decrease of Ca(2+) spark frequency by superoxide dismutase (SOD). O(2)(-). generated in situ from the xanthine/xanthine oxidase reaction caused a slowly developing decrease of Ca(2+) spark frequency and SR Ca(2+) load by 44% and 32%, respectively. Furthermore, in studies with cardiac SR microsomes NADH slowed the rate of ATP-dependent Ca(2+) uptake by 39%. This effect also appeared to depend on O(2)(-). formation. Single channel recordings from RyRs incorporated into lipid bilayers revealed that NADH (2 mm) inhibited the activity of RyR channels by 84%. However, NADH inhibition of RyR activity was O(2)(-).-independent. In summary, an increase of the cytoplasmic NADH/NAD(+) ratio depresses SR Ca(2+) release in ventricular cardiomyocytes. The effect appears to be mediated by direct NADH inhibition of RyR channel activity and by indirect NADH inhibition (O(2)(-). mediated) of SR Ca(2+)-ATPase activity with a subsequent decrease in SR Ca(2+) content.
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PMID:Effects of cytosolic NADH/NAD(+) levels on sarcoplasmic reticulum Ca(2+) release in permeabilized rat ventricular myocytes. 1472 8

S-Nitrosylation is a ubiquitous post-translational modification that regulates diverse biologic processes. In skeletal muscle, hypernitrosylation of the ryanodine receptor (RyR) causes sarcoplasmic reticulum (SR) calcium leak, but whether abnormalities of cardiac RyR nitrosylation contribute to dysfunction of cardiac excitation-contraction coupling remains controversial. In this study, we tested the hypothesis that cardiac RyR2 is hyponitrosylated in heart failure, because of nitroso-redox imbalance. We evaluated excitation-contraction coupling and nitroso-redox balance in spontaneously hypertensive heart failure rats with dilated cardiomyopathy and age-matched Wistar-Kyoto rats. Spontaneously hypertensive heart failure myocytes were characterized by depressed contractility, increased diastolic Ca(2+) leak, hyponitrosylation of RyR2, and enhanced xanthine oxidase derived superoxide. Global S-nitrosylation was decreased in failing hearts compared with nonfailing. Xanthine oxidase inhibition restored global and RyR2 nitrosylation and reversed the diastolic SR Ca(2+) leak, improving Ca(2+) handling and contractility. Together these findings demonstrate that nitroso-redox imbalance causes RyR2 oxidation, hyponitrosylation, and SR Ca(2+) leak, a hallmark of cardiac dysfunction. The reversal of this phenotype by inhibition of xanthine oxidase has important pathophysiologic and therapeutic implications.
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PMID:Impaired S-nitrosylation of the ryanodine receptor caused by xanthine oxidase activity contributes to calcium leak in heart failure. 2064 51