Title: Genomic modulation of mitochondrial respiratory genes in the hypertrophied heart reflects adaptive changes in mitochondrial and contractile function Authors
|Makhosazane, Zungu -|
|Alcolea, Maria -|
|Garcia-Palmer, Francisco -|
|Young, Martin -|
|Essop, M -|
Submitted to: American Journal of Physiology - Heart and Circulatory Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 10, 2007
Publication Date: August 17, 2007
Citation: Makhosazane, Z., Alcolea, M.P., Garcia-Palmer, F.J., Young, M.E., Essop, M.F. 2007. Genomic modulation of mitochondrial respiratory genes in the hypertrophied heart reflects adaptive changes in mitochondrial and contractile function. American Journal of Physiology - Heart and Circulatory Physiology. 293(5):H2819-H2825. Interpretive Summary: An inability of the heart to pump enough blood is termed heart failure. One possible explanation for heart failure is that the heart is not able to generate enough energy. Problems with fatty acid metabolism have been suggested. This study investigated whether genes known to be critical for energy metabolism are altered in an animal model of heart disease. The data show that during the early stages of heart disease, the heart attempts to adapt metabolically, in order to maintain energy production. The implications are that a failure to maintain activation of these adaptation processes may trigger energy insufficiency, and therefore contractile dysfunction.
Technical Abstract: 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% O(2)) 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 O(2) 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-gamma-coactivator-1alpha, 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.