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Mitochondrial integrity in a neonatal bovine model of right ventricular dysfunction

Bruns DR1, Brown RD2, Stenmark KR2, Buttrick PM1, Walker LA3. Am J Physiol Lung Cell Mol Physiol. 2015 Jan 15;308(2):L158-67.

1Department of Medicine, Cardiology, University of Colorado-Denver, Aurora, Colorado;

2Department of Pediatrics, University of Colorado-Denver, Aurora, Colorado.

3Department of Medicine, Cardiology, University of Colorado-Denver, Aurora, Colorado; and [email protected]

 

Abstract

Right ventricular (RV) function is a key determinant of survival in patients with both RV and left ventricular (LV) failure, yet the mechanisms of RV failure are poorly understood. Recent studies suggest cardiac metabolism is altered in RV failure in pulmonary hypertension (PH). Accordingly, we assessed  mitochondrial content, dynamics, and function in hearts from neonatal calves exposed to hypobaric hypoxia (HH). This model develops severe PH with concomitant RV hypertrophy, dilation, and dysfunction. After 2 wk of HH, pieces of RV and LV were obtained along with samples from age-matched controls. Comparison with control assesses the effect of hypoxia, whereas comparison between the LV and RV in HH assesses the additional impact of RV overload. Mitochondrial DNA was unchanged in HH, as was  mitochondrial content as assessed by electron microscopy. Immunoblotting for electron transport chain subunits revealed a small increase in  mitochondrial content in HH in both ventricles. Mitochondrial dynamics were largely unchanged. Activity of individual respiratory chain complexes was reduced (complex I) or unchanged (complex V) in HH. Key enzymes in the glycolysis pathway were upregulated in both HH ventricles, alongside upregulation of hypoxia-inducible factor-1α protein. Importantly, none of the changes in expression or activity were different between ventricles, suggesting the changes are in response to HH and not RV overload. Upregulation of glycolytic modulators without chamber-specific  mitochondrial  dysfunction  suggests that mitochondrial capacity and activity are maintained  at  the onset of PH, and the early RV dysfunction in this model results from mechanisms independent of the mitochondria.

Copyright © 2015 the American Physiological Society.

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