ADMA/NO endothelial pathway in hypoxia-associated chronic respiratory diseasesAuthor(s): Luneburg Nicole
Since its discovery, it is widely believed that Asymmetric Di Methyl Arginine (ADMA), as an inhibitor of Nitric Oxide (NO) synthesis, contributes to the pathogenesis of various diseases. This is especially evident in diseases of the cardiovascular system, where endothelial dysfunction leads to an imbalance between vasoconstriction and vasodilation. Although increased ADMA levels are strongly associated with endothelial dysfunction, several studies have pointed to a potentially beneficial effect of ADMA, primarily in the context of angiogenic diseases such as cancer and fibrosis chemical. The NO-independent anti proliferative properties of ADMA were identified in this setting. In particular, the regulation of ADMA by the degrading enzyme Dimethyl Arginine Dimethyl Amino Hydrolase (DDAH) has been the subject of many studies. DDAH is considered a promising therapeutic target for the indirect regulation of NO. In hypoxia-associated chronic respiratory disease, this controversial discussion of ADMA and DDAH is particularly clear-cut and is therefore the focus of this review. Endothelial-derived NO is known to be a major mediator of vasomotor tone regulation. NO is involved in a variety of mechanisms with regulatory functions, including inhibition of platelet adhesion and aggregation, monocyte adhesion, and smooth muscle cell proliferation. Therefore, NO plays an important role in vascular homeostasis. NO is produced by Nitric Oxide Synthase (NOS) enzymes. There are three distinct isomers that catalyze the formation of NO from the L-arginine and O2 substrates, with L-citrulline being generated as a second product. The distinct isoforms differ in their tissue and cellular distribution and regulatory mechanisms. The three isoforms are neuronal NOS (NOS1, nNOS), inducible NOS (NOS2, iNOS) and endothelial NOS (NOS3, eNOS). Among others, nNOS is mainly expressed in the central and peripheral nervous system, kidney, pancreas, and skeletal muscle. The induced form of NOS was initially identified as a mediator of innate immunity and macrophages and can be induced in different cell types such as vascular smooth muscle cells, renal tubular epithelium, hepatocytes and mesenchymal cells. Expression of eNOS is mainly limited to vascular endothelial cells and mainly to medium and large sized arteries and arterioles.