Role of the PRMT-DDAH-ADMA axis in the regulation of endothelial nitric oxide production

Pharmacol Res. 2009 Dec;60(6):461-5. doi: 10.1016/j.phrs.2009.07.016. Epub 2009 Aug 12.


There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO), formed in healthy vascular endothelium from the amino acid precursor l-arginine. Endothelial dysfunction is increased by various cardiovascular risk factors, metabolic diseases, and systemic or local inflammation. One mechanism that has been implicated in the development of endothelial dysfunction is the presence of elevated levels of asymmetric dimethylarginine (ADMA). Free ADMA, which is formed during proteolysis, is actively degraded by the intracellular enzyme dimethylarginine dimethylaminohydrolase (DDAH) which catalyzes the conversion of ADMA to citrulline and dimethylamine. It has been estimated that more than 70% of ADMA is metabolized by DDAH (Achan et al. [1]). Decreased DDAH expression/activity is evident in disease states associated with endothelial dysfunction and is believed to be the mechanism responsible for increased methylarginines and subsequent ADMA mediated eNOS impairment. However, recent studies suggest that DDAH may regulate eNOS activity and endothelial function through both ADMA-dependent and -independent mechanisms. In this regard, elevated plasma ADMA may serve as a marker of impaired methylarginine metabolism and the pathology previously attributed to elevated ADMA may be manifested, at least in part, through altered activity of the enzymes involved in ADMA regulation, specifically DDAH and PRMT.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Amidohydrolases / physiology*
  • Animals
  • Arginine / analogs & derivatives*
  • Arginine / physiology
  • Biomarkers / metabolism
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / enzymology
  • Cardiovascular Diseases / pathology
  • Endothelium, Vascular / enzymology
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Humans
  • Nitric Oxide / biosynthesis*
  • Nitric Oxide / physiology
  • Nitric Oxide Synthase Type III / biosynthesis*
  • Protein-Arginine N-Methyltransferases / physiology*


  • Biomarkers
  • Nitric Oxide
  • N,N-dimethylarginine
  • Arginine
  • Nitric Oxide Synthase Type III
  • Protein-Arginine N-Methyltransferases
  • Amidohydrolases
  • dimethylargininase