Novel insights into interactions between mitochondria and xanthine oxidase in acute cardiac volume overload.

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. Copyright © 2011. Published by Elsevier Inc.

Citation

James D Gladden, Blake R Zelickson, Chih-Chang Wei, Elena Ulasova, Junying Zheng, Mustafa I Ahmed, Yuanwen Chen, Marcas Bamman, Scott Ballinger, Victor Darley-Usmar, Louis J Dell'Italia. Novel insights into interactions between mitochondria and xanthine oxidase in acute cardiac volume overload. Free radical biology & medicine. 2011 Dec 1;51(11):1975-84

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PMID: 21925594

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