Mitochondrial metabolic adaptation in right ventricular hypertrophy and failure

Lin Piao, Glenn Marsboom, Stephen L Archer
Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte" 2010, 88 (10): 1011-20
Right ventricular failure (RVF) is the leading cause of death in pulmonary arterial hypertension (PAH). Some patients with pulmonary hypertension are adaptive remodelers and develop RV hypertrophy (RVH) but retain RV function; others are maladaptive remodelers and rapidly develop RVF. The cause of RVF is unclear and understudied and most PAH therapies focus on regressing pulmonary vascular disease. Studies in animal models and human RVH suggest that there is reduced glucose oxidation and increased glycolysis in both adaptive and maladaptive RVH. The metabolic shift from oxidative mitochondrial metabolism to the less energy efficient glycolytic metabolism may reflect myocardial ischemia. We hypothesize that in maladaptive RVH a vicious cycle of RV ischemia and transcription factor activation causes a shift from oxidative to glycolytic metabolism thereby ultimately promoting RVF. Interrupting this cycle, by reducing ischemia or enhancing glucose oxidation, might be therapeutic. Dichloroacetate, a pyruvate dehydrogenase kinase inhibitor, has beneficial effects on RV function and metabolism in experimental RVH, notably improving glucose oxidation and enhancing RV function. This suggests the mitochondrial dysfunction in RVH may be amenable to therapy. In this mini review, we describe the role of impaired mitochondrial metabolism in RVH, using rats with adaptive (pulmonary artery banding) or maladaptive (monocrotaline-induced pulmonary hypertension) RVH as models of human disease. We will discuss the possible mechanisms, relevant transcriptional factors, and the potential of mitochondrial metabolic therapeutics in RVH and RVF.

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