From arginine methylation to ADMA: A novel mechanism with therapeutic potential in chronic lung diseases

Protein arginine methylation is a novel posttranslational modification regulating a diversity of cellular processes, including protein-protein interaction, signal transduction, or histone function. It has recently been shown to be dysregulated in chronic renal, vascular, and pulmonary diseases, and metabolic products originating from protein arginine methylation have been suggested to serve as biomarkers in cardiovascular and pulmonary diseases. Protein arginine methylation is performed by a class of enzymes called protein arginine methyltransferases (PRMT), which specifically methylate protein-incorporated arginine residues to generate protein-incorporated monomethylarginine (MMA), symmetric dimethylarginine (SDMA), or asymmetric dimethylarginine (ADMA). Upon proteolytic cleavage of arginine-methylated proteins, free intracellular MMA, SDMA, or ADMA is generated, which, upon secretion into the extracellular space (including plasma), directly affects the methylarginine concentration in the plasma. Free methylarginines are cleared from the body by renal excretion or hepatic metabolism. In addition, MMA and ADMA, but not SDMA, can be degraded via a class of intracellular enzymes called dimethylarginine dimethylaminohydrolases (DDAH). ADMA and MMA are endogenous inhibitors of nitric oxide synthases (NOS) and ADMA has been suggested to serve as a biomarker of endothelial dysfunction in cardiovascular diseases. This view has now been extended to the idea that, in addition to serum ADMA, the amount of free, as well as protein-incorporated, intracellular ADMA influences pulmonary cell function and determines the development of chronic lung diseases, including pulmonary arterial hypertension (PAH) or pulmonary fibrosis. This review will present and discuss the recent findings of dysregulated arginine methylation in chronic lung disease. We will highlight novel directions for future investigations evaluating the functional contribution of arginine methylation in lung homeostasis and disease with the outlook that modifying PRMT or DDAH activity presents a novel therapeutic option for the treatment of chronic lung disease.