title: Novel insights into interactions between mitochondria and xanthine oxidase in acute cardiac volume overload.
abstract: Xanthine oxidoreductase (XOR) is increased in the left ventricle (LV) of humans with volume overload (VO), and mitochondrial inhibition of the respiratory chain occurs in animal models of VO. Because mitochondria are both a source and a target of reactive oxygen and nitrogen species, we hypothesized that activation of XOR and mitochondrial dysfunction are interdependent. To test this we used the aortocaval fistula (ACF) rat model of VO and a simulation of the stretch response in isolated adult cardiomyocytes with and without the inhibitor of XOR, allopurinol, or the mitochondrially targeted antioxidant MitoQ. Xanthine oxidase (XO) activity was increased in cardiomyocytes from ACF vs sham rats (24h) without an increase in XO protein. A twofold increase in LV end-diastolic pressure/wall stress and a decrease in LV systolic elastance with ACF were improved when allopurinol treatment (100mg/kg) was started at ACF induction. Subsarcolemmal State 3 mitochondrial respiration was significantly decreased in ACF and normalized by allopurinol. Cardiomyocytes subjected to 3h cyclical stretch resulted in an increase in XO activity and mitochondrial swelling, which was prevented by allopurinol or MitoQ pretreatment. These studies establish an early interplay between cardiomyocyte XO activation and bioenergetic dysfunction that may provide a new target that prevents progression to heart failure in VO.
authors.affiliation: Center for Heart Failure Research, University of Alabama at Birmingham, Birmingham, AL 35294-2180, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Gladden
authors.forename: Blake R
authors.initials: BR
authors.lastname: Zelickson
authors.forename: Chih-Chang
authors.initials: CC
authors.lastname: Wei
authors.forename: Elena
authors.initials: E
authors.lastname: Ulasova
authors.forename: Junying
authors.initials: J
authors.lastname: Zheng
authors.forename: Mustafa I
authors.initials: MI
authors.lastname: Ahmed
authors.forename: Yuanwen
authors.initials: Y
authors.lastname: Chen
authors.forename: Marcas
authors.initials: M
authors.lastname: Bamman
authors.forename: Scott
authors.initials: S
authors.lastname: Ballinger
authors.forename: Victor
authors.initials: V
authors.lastname: Darley-Usmar
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Dell'Italia
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001164:Arteriovenous Fistula / Q000378:metabolism*; D002306:Cardiac Volume; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D000493:Allopurinol; D014969:Xanthine Oxidase