B05
Importance of mitochondrial ROS and substrate metabolism for the development and progression of right heart failure
Increased mitochondrial reactive oxygen species (ROS) formation and a metabolic switch directing heart metabolism from fatty acid to carbohydrate consumption are important for the development of right ventricular (RV) hypertrophy (RVH) and failure (RVF) during pulmonary hypertension (PH). Differences in the expression of proteins that contribute to either mitochondrial ROS formation or metabolism exist between species, organs and on the level of the heart, between ventricles. The latter might help to explain differences between pressure adaptation of the right and left heart and might help to identify promising candidates for targeted therapy of RVF. Mechanical load as the first hit of PH reduces the expression of pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) shifting oxidative glucose metabolism to glycolysis thereby feeding branch pathways required for protein synthesis and subsequently RVH. As a consequence, RV cardiomyocytes lose energy production by oxidative phosphorylation of glucose but compensate by activation of uncoupling protein (UCP) 2, thereby enhancing β-oxidation. However, the high sensitivity of RV cardiomyocytes to mechanical stress triggers a moderate cell damage and subsequently local inflammation, the second hit caused by PH. Activation of local neurohumoral systems and the increased number of inflammatory cells, including mast cells, within the right ventricle enhances oxidative stress in part through activated monoamine oxidases (MAOs) within cardiomyocytes. Increased oxidative stress and local inflammation reduce UCP2 expression, thereby limiting β-oxidation. We showed previously that cardiomyocytes try to compensate for decreased fatty acid oxidation by increasing glucose uptake and oxidative glucose metabolism, but the latter effect is limited in the right ventricle due to reduction of PDHA1, thereby further supporting feeding of branch pathways and anaerobic glycolysis. Furthermore, RVH promotes the down-regulation of RC3H2, a gene coding for the protein roquin-2, in an UCP2-dependent way. This activates protein synthesis but also affects micro RNA (miR) expression and thereby affects cardiac remodeling in a more general way, specifically in the right ventricle. Based on these findings, central questions for the progression of the project are to 1) decipher the interaction between PDHA1 and UCP2, 2) validate the link between UCP2-dependent metabolic alterations and protein synthesis and hypertrophy, 3) investigate the RV adaptation to volume load, 4) further investigate the relationship between MAO-dependent substrate availability and utilization for RHF development, and 5) to clarify whether blockade of MAO-dependent ROS formation reverses PH-induced cardiac alterations even after first signs of the disease have developed. Using state-of-the-art technologies (e.g. metabolome analysis, stress exposure in vitro [single cell level] and in vivo in genetic modified rats and mice) will allow to identify the fundamental molecular adaptations and signal transduction pathways underlying RVH and RVF, and by comparison to alterations measured in human hearts from PH, to identify promising pathways as potential treatment targets.
