title: Chronic xanthine oxidase inhibition prevents myofibrillar protein oxidation and preserves cardiac function in a transgenic mouse model of cardiomyopathy.
abstract: Heart failure is a clinical syndrome associated with elevated levels of oxygen-derived free radicals. Xanthine oxidase activity is believed to be one source of reactive oxygen species in the failing heart. Interventions designed to reduce oxidative stress are believed to have significant therapeutic potential in heart failure. This study tested the hypothesis that xanthine oxidase activity would be elevated in a mouse model of dilated cardiomyopathy and evaluated the effect of chronic oral allopurinol, an inhibitor of xanthine oxidase, on contractility and progressive ventricular dilation in these mice. Nontransgenic and transgenic mice containing a troponin I truncation were treated with oral allopurinol from 2-4 mo of age. Myocardial xanthine oxidase activity was threefold higher in untreated transgenic mice compared with nontransgenic mice. Analyses of myofilament proteins for modification of carbonyl groups demonstrated myofibrillar protein damage in untreated transgenic mice. Treatment with allopurinol for 2 mo suppressed xanthine oxidase activity and myofibrillar protein oxidation. Allopurinol treatment also alleviated ventricular dilation and preserved shortening fraction in the transgenic animals. In addition, cardiac muscle twitch tension was preserved to 70% of nontransgenic levels in allopurinol-treated transgenic mice, a significant improvement over untreated transgenic mice. These findings indicate that chronic inhibition of xanthine oxidase can alter the progression of heart failure in dilated cardiomyopathy.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Duncan
authors.forename: Rajashree
authors.initials: R
authors.lastname: Ravi
authors.forename: Linda B
authors.initials: LB
authors.lastname: Stull
authors.forename: Anne M
authors.initials: AM
authors.lastname: Murphy
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000201:enzymology; D009210:Myofibrils / Q000201:enzymology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D019210:Troponin I / Q000235:genetics; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D019210:Troponin I; D000493:Allopurinol; D014969:Xanthine Oxidase