The Second Life of Methylarginines as Cardiovascular Targets

Abstract

Endogenous methylarginines were proposed as cardiovascular risk factors more than two decades ago, however, so far, this knowledge has not led to the development of novel therapeutic approaches. The initial studies were primarily focused on the endogenous inhibitors of nitric oxide synthases asymmetric dimethylarginine (ADMA) and monomethylarginine (MMA) and the main enzyme regulating their clearance dimethylarginine dimethylaminohydrolase 1 (DDAH1). To date, all the screens for DDAH1 activators performed with the purified recombinant DDAH1 enzyme have not yielded any promising hits, which is probably the main reason why interest towards this research field has started to fade. The relative contribution of the second DDAH isoenzyme DDAH2 towards ADMA and MMA clearance is still a matter of controversy. ADMA, MMA and symmetric dimethylarginine (SDMA) are also metabolized by alanine: glyoxylate aminotransferase 2 (AGXT2), however, in addition to methylarginines, this enzyme also has several cardiovascular protective substrates, so the net effect of possible therapeutic targeting of AGXT2 is currently unclear. Recent studies on regulation and functions of the enzymes metabolizing methylarginines have given a second life to this research direction. Our review discusses the latest discoveries and controversies in the field and proposes novel directions for targeting methylarginines in clinical settings.

Activated L-Arginine/Nitric Oxide Pathway in Pediatric Cystic Fibrosis and Its Association with Pancreatic Insufficiency, Liver Involvement and Nourishment: An Overview and New Results

“…MMA, ADMA and SDMA are released during the proteolysis of certain NG-methylated proteins [52,54]. MMA is found in blood and urine at concentrations a 10th of the ADMA and SDMA concentrations [55,56]. ADMA and SDMA are considered atherosclerotic risk factors [51].…”

ADMA: A Key Player in the Relationship between Vascular Dysfunction and Inflammation in Atherosclerosis

“…ADMA and L-NMMA have been of interest to vascular scientists since they were shown to be endogenous inhibitors of nitric oxide synthase (NOS) via competition with L-arginine, the requisite NOS substrate and structural analogue of ADMA and L-NMMA [1,13]. In healthy serum, the concentration of ADMA is between 0.4 and 0.6 µM [14]; in contrast, the serum concentration of L-NMMA is 5-10 fold lower at~0.05 µM [15]. The third methylarginine SDMA is found at concentrations similar to that of ADMA [14].…”

“…Albeit that SDMA is not a direct inhibitor of NOS, SDMA can still alter L-arginine concentrations via competition at amino acid transporters. However, the biological relevance of this and further unknown mechanisms still needs to be investigated to fully understand how SDMA affects clinical outcome [15].…”

Role of Asymmetric Dimethylarginine and Nitric Oxide in Type 2 Diabetes Mellitus and Its Cardiovascular Complications

“…Also, Taner et al (2013) indicated that serum ADMA may play a role in both the pathophysiology and screening of masked hypertension in diabetic subjects. Accordingly, future therapeutic strategies that could be used to target NOS (Daiber et al, 2019) and/or DDAH (Jarzebska et al, 2019) activity could be promising in the management of cardiovascular and other vascular complications of diabetes mellitus.…”