ADMA and the role of the genes: lessons from genetically modified animals and human gene polymorphisms.
In large population-based cohorts, elevated plasma levels of asymmetric dimethylarginine (ADMA) were found to be associated with cardiovascular events and mortality. Impairment of nitric oxide (NO) synthesis from l-arginine has been postulated as underlying mechanism. In the present review, we compare different experimental models of NOS deficiency or overexpression with corresponding models of altered metabolism of ADMA by dimethylarginine dimethylaminohydrolase (DDAH). The latter models show a considerable overlap with the pathophysiological features of impaired NO synthesis, such as impaired endothelial function, elevation of blood pressure, and microvascular fibrosis. In line with these findings, first data regarding genetic variation of DDAH-metabolism in humans are reminiscent of the (rather modest) effects previously observed with polymorphisms of the eNOS gene. However, several peculiar observations suggest that ADMA- or DDAH-related pathology may extend beyond impairment of NO-mediated signalling. Notably, the complete knock out of DDAH1 appears to be lethal while triple NOS(-/-) mice are viable. Moreover, some ADMA-mediated pathology appears to respond rather to ACE-inhibition than to l-arginine. Here, a further investigation of alternative target enzymes for ADMA and other endogenous DDAH substrates is warranted.Taken together, the current data suggest that ADMA-related pathology can largely but not completely be explained by impaired NO metabolism.
Maas
Renke
R
Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander University, Erlangen-Nuremberg, Germany. renke.maas@pharmakologie.uni-erlangen.de
Böger
Rainer
R
Lüneburg
Nicole
N
D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics* / Q000502:physiology; D001120:Arginine / Q000031:analogs & derivatives* / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D011110:Polymorphism, Genetic / Q000235:genetics* / Q000502:physiology
C018524:N,N-dimethylarginine; D001120:Arginine