Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 51, Issue 11, Pages 1975-1984Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2011.08.022
Keywords
Volume overload; Oxidative stress; MitoQ; Stretch; Mitochondria; Allopurinol; Free radicals
Funding
- NHLBI [RO1 HL54816]
- Specialized Center of Clinically Orientated Research in Cardiac Dysfunction [P50HL077100]
- National Institutes of Health [T 32 HL007918]
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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 VU. 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 VU 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 (24 h) 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 (100 mg/kg) was started at ACF induction. Subsarcolemmal State 3 mitochondrial respiration was significantly decreased in ACF and normalized by allopurinol. Cardiomyocytes subjected to 3 h 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. (C) 2011 Published by Elsevier Inc.
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