Right ventricular dysfunction is the most frequent cause of death in patients with pulmonary arterial hypertension. Although abnormal energy substrate use has been implicated in the development of chronic left heart failure, data describing such metabolic remodeling in failing right ventricular tissue remain incomplete. In the present dissertation we sought to characterize metabolic gene expression changes and mitochondrial dysfunction in functional and dysfunctional RV hypertrophy. Two different rat models of RV hypertrophy were studied. The model of right ventricular failure (SU5416/hypoxia) exhibited a significantly decreased gene expression of peroxisome proliferator-activated receptor- coactivator-1α, peroxisome proliferator- activated receptor-α and estrogen-related receptor-α. The expression of multiple peroxisome proliferator-activated receptor- coactivator-1α target genes required for fatty acid oxidation was similarly decreased. Decreased peroxisome proliferator-activated receptor- coactivator-1α expression was also associated with a net loss of mitochondrial protein and oxidative capacity. Reduced mitochondrial number was associated with a downregulation of transcription factor A, mitochondrial, and other genes required for mitochondrial biogenesis. Electron microscopy demonstrated that, in right ventricular failure tissue, mitochondria had abnormal shape and size. Lastly, respirometric analysis demonstrated that mitochondria isolated from right ventricular failure tissue had a significantly reduced ADP- stimulated (state 3) rate for complex I. Conversely, functional right ventricular hypertrophy in the pulmonary artery banding model showed normal expression of peroxisome proliferator-activated receptor- coactivator-1α, whereas the expression of fatty acid oxidation genes was either preserved or unregulated. Moreover, pulmonary artery banding-right ventricular tissue exhibited preserved transcription factor A mitochondrial expression and mitochondrial respiration despite elevated right ventricular pressure-overload. We conclude that right ventricular dysfunction, but not functional right ventricular hypertrophy in rats, demonstrates a gene expression profile compatible with a multilevel impairment of fatty acid metabolism and significant mitochondrial dysfunction, partially independent of chronic pressure-overload.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-4256 |
| Date | 04 December 2013 |
| Creators | Gomez-Arroyo, Jose |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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