University of Giessen Lung Center

The DDAH-ADMA-NOS pathway

Cardiopulmonary diseases are major global health problems that have an increasing disease burden and effect on health-care spending. One common characteristic is endothelial dysfunction which leads to an abnormal response to shear stress and maldistribution of perfusion to flow demanding areas within the cardiopulmonary system. It has been shown that increased levels of dimethylated arginines (DMA), derived from protein arginine N-methyltransferases (PRMT’s) inhibit endothelial nitric oxide synthase (eNOS), thereby promoting the endothelial dysfunction. Furthermore, the DMA cleaving enzyme dimethylarginine dimethylaminohydrolase (DDAH) is downregulated in several diseases (e.g. atherosclerosis, pulmonary hypertension, diabetes). Thus, enhanced generation and/or reduced metabolism of dimethylated arginines may contribute to NOS inhibition and thereby loss of vessel patency in cardiopulmonary diseases. The aim of this project is to analyse the expression (mRNA and protein level; compartment- and cell-specifity) and activity of the DDAH isoforms in cells and tissue (PH tissue bank core facility Giessen) and to investigate pharmacological approaches to increase DDAH activity in preclinical models of cardiopulmonary diseases. Agents of interest will be tested in the various experimental models, and candidates for phase I/II trials aiming to influence the DDAH-ADMA-NOS axis will be evaluated.