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Genomic modulation of mitochondrial respiratory genes in the hypertrophied heart reflects adaptive changes in mitochondrial and contractile function

¹Hatter Heart Research Institute, Department of Medicine, University of Cape Town Faculty of Health Sciences, Cape Town, South Africa; ²Grup de Metabolisme Energètic i Nutrició, Universitat de les Illes Balears, Palma de Mallorca, and Ciber Fisiopathologia, and Centro de Investigación Biomédica en Red Fisiopatología Obesidad y Nutrición (CB06/03), Instituto Salud Carlos III, Spain; ³United States Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas; and ⁴Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa

Submitted 28 July 2006 ; accepted in final form 10 August 2007

We hypothesized the coordinate induction of mitochondrial regulatory genes in the hypertrophied right ventricle to sustain mitochondrial respiratory capacity and contractile function in response to increased load. Wistar rats were exposed to hypobaric hypoxia (11% O₂) or normoxia for 2 wk. Cardiac contractile and mitochondrial respiratory function were separately assessed for the right and left ventricles. Transcript levels of several mitochondrial regulators were measured. A robust hypertrophic response was observed in the right (but not left) ventricle in response to hypobaric hypoxia. Mitochondrial O₂ consumption was increased in the right ventricle, while proton leak was reduced vs. normoxic controls. Citrate synthase activity and mitochondrial DNA content were significantly increased in the hypertrophied right ventricle, suggesting higher mitochondrial number. Transcript levels of nuclear respiratory factor-1, peroxisome proliferator-activated receptor--coactivator-1, cytochrome oxidase (COX) subunit II, and uncoupling protein-2 (UCP2) were coordinately induced in the hypertrophied right ventricle following hypoxia. UCP3 transcript levels were significantly reduced in the hypertrophied right ventricle vs. normoxic controls. Exposure to chronic hypobaric hypoxia had no significant effects on left ventricular mitochondrial respiration or contractile function. However, COXIV and UCP2 gene expression were increased in the left ventricle in response to chronic hypobaric hypoxia. In summary, we found coordinate induction of several genes regulating mitochondrial function and higher mitochondrial number in a model of physiological right ventricular hypertrophy, linking the efficiency of mitochondrial oxidative phosphorylation and respiratory function to sustained contractile function in response to the increased load.

gene expression; mitochondria; hypertrophy; hypobaric hypoxia

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