Role of Dimethylarginine Dimethylaminohydrolase (DDAH) in vascular and parenchymal lung diseases

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The process of protein metabolism accumulates asymmetric and symmetric dimethylarginines (ADMA, SDMA), which impact the activity of nitric oxide synthases (NOS). These endogenous inhibitors undergo either renal elimination, or are degraded by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). The objective of this project is to investigate the role of DDAH in the pathobiology of pulmonary vascular and parenchymal diseases. The overall hypothesis of this project is that DDAH-ADMA axis is differently regulated in different forms of pulmonary hypertension (PH), for example in pulmonary arterial hypertension (PAH) versus PH associated with lung fibrosis. While there is already some evidence that in the PAH a down-regulation of DDAH results in progression of PH and up-regulation of DDAH is observed in parenchymal fibro-proliferative disorders, the role of DDAH in the context of PH associated with lung fibrosis remains unknown. On the level of animal models, human lung samples and comprehensive in vitro approaches, we will profoundly investigate this scientific issue. We also aim to unravel a novel signaling cascade potentially responsible for beneficial therapeutic effects of cGMP elevating agents in experimental PAH. In addition, we will address DDAH regulatory mechanisms and investigate the effects of proton pump inhibitors (which are DDAH inhibitors) in experimental pulmonary fibrosis.