Interaction of ROS sources, mitochondrial biogenesis and redox-signaling in pulmonary hypertension.

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Alveolar hypoxia in the lung leads to hypoxic pulmonary vasoconstriction (HPV), which, if localized, matches blood perfusion to alveolar ventilation and thus optimizes pulmonary gas exchange. In contrast in chronic, generalized hypoxia this effect is lost and leads to pulmonary hypertension. Alveolar hypoxia accompanies a plethora of lung diseases. Generation of reactive oxygen species (ROS) has been suggested to play a key role in hypoxia- but also in non-hypoxia-induced pulmonary hypertension (PH) as well as chronic obstructive pulmonary disease (COPD). As ROS sources mitochondria and NADPH oxidases (NOX1, NOX2 and NOX4) have now been identified by us and others, with different impact on the different phases of the hypoxia effects. In addition we identified multiple downstream signaling mechanisms of alveolar hypoxia. Based on our findings the goal of the renewal proposal is to now address the interaction of mitochondria and NADPH oxidases, to further decipher their molecular oxygen sensing properties, to assess the subcellular distribution of ROS and ROS production in microdomains (caveolae) for the above processes. Downstream signaling mechanisms will be further delineated and newly identified mediators will be validated as targets for the above signaling processes. In addition the impact of other gasotransmitters like hydrogen sulfide (H2S) on target structures of redox-sensitive pathways will be investigated.