Mitochondrial metabolic adaptation in right ventricular hypertrophy and failure

Abstract

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.

Cardiac Energy Metabolic Alterations in Pressure Overload–Induced Left and Right Heart Failure (2013 Grover Conference Series)

“…As in the left ventricle, the right ventricle develops hypertrophy in response to pressure overload. 8,17,20 Due to the thin wall, the right ventricle undergoes rapid and exaggerated hypertrophic response. 81 Following hypertrophy, the right ventricle undergoes dilatation resulting in decreased contractile force, ultimately resulting in right ventricular failure.…”

“…17,20 Similar to the left ventricle, the right ventricle also primarily depends on mitochondrial oxidative phosphorylation for ATP production from fatty acids and glucose. 8,81 Right heart failure is also associated with low ATP production. 82,83 Energy deficit in right ventricular hypertrophy and failure Right ventricular hypertrophy (RVH) and failure are associated with a switch from oxidative metabolism to glycolysis.…”

Effect of siRNA silencing of inducible co-stimulatory molecule on myocardial cell hypertrophy after cardiac infarction in rats

“…We then utilized siRNA methods to specifically down-regulate ICOS gene expression (Hasenfuss, 1998;Piao et al, 2010;Georgiopoulou et al, 2013;Kazi and Mark, 2013;Mandel and Poch, 2013). The small molecule siRNA can specifically induce the degradation of target genes under certain circumstances, leading to the down-regulation of target genes and related biological functions, all of which may be associated with the occurrence of myocardial hypertrophy (Hunt et al, 2001;Yanazume et al, 2002;Mita et al, 2005;Rosamond et al, 2008).…”

An Official American Thoracic Society Statement: Pulmonary Hypertension Phenotypes

“…The ideal endophenotype is reliably assessed, is stable over time, is associated with the disease of interest, and is at least as heritable as the disease itself (9). Levels of oxidative stress, endothelial dysfunction, and mitochondrial dysfunction are potential endophenotypes that may be shared among PH, cancer, and systemic vascular disease (10)(11)(12)(13)(14)(15)(16)(17). Although it is traditional to establish the phenotype by its observable traits and then to search for genetic associations, the genetic or molecular markers can be used to identify the phenotype, that is, reverse phenotyping.…”