Redefining the biological and pathophysiological role of dimethylarginine dimethylaminohydrolase 2

The enzyme dimethylarginine dimethylaminohydrolase (DDAH) 1 plays the key role in the metabolism of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis and inducer of superoxide production.The role of the second DDAH isoform DDAH2 in the metabolism of ADMA has been debated; however, recent studies have conclusively demonstrated that this isoform cannot hydrolyze ADMA.The DDAH2 protein regulates several processes associated with cardiometabolic homeostasis, immune function, and other tasks independent of ADMA.DDAH2 has been demonstrated to improve cardiac function, stabilize atherosclerotic plaques, facilitate the regeneration of damaged endothelium in animal models, regulate insulin production, and protect from sepsis.It is crucial to understand the molecular mechanism of DDAH2 to unravel its biological functions and identify novel therapeutic opportunities. The enzyme dimethylarginine dimethylaminohydrolase (DDAH) 1 metabolizes asymmetric dimethylarginine (ADMA), a critical endogenous cardiovascular risk factor. In the past two decades, there has been significant controversy about whether DDAH2, the other DDAH isoform, is also able to directly metabolize ADMA. There has been evidence that DDAH2 regulates several critical processes involved in cardiovascular and immune homeostasis. However, the molecular mechanisms underpinning these effects are unclear. In this opinion, we discuss the previous and current knowledge of ADMA metabolism by DDAH in light of a recent consortium study, which convincingly demonstrated that DDAH2 is not capable of metabolizing ADMA, unlike DDAH1. Thus, further research in this field is needed to uncover the molecular mechanisms of DDAH2 and its role in various disorders. The enzyme dimethylarginine dimethylaminohydrolase (DDAH) 1 metabolizes asymmetric dimethylarginine (ADMA), a critical endogenous cardiovascular risk factor. In the past two decades, there has been significant controversy about whether DDAH2, the other DDAH isoform, is also able to directly metabolize ADMA. There has been evidence that DDAH2 regulates several critical processes involved in cardiovascular and immune homeostasis. However, the molecular mechanisms underpinning these effects are unclear. In this opinion, we discuss the previous and current knowledge of ADMA metabolism by DDAH in light of a recent consortium study, which convincingly demonstrated that DDAH2 is not capable of metabolizing ADMA, unlike DDAH1. Thus, furt