The Role of Asymmetric Dimethylarginine and Arginine in the Failing Heart and its Vasculature

Marlieke Visser; Walter J. Paulus; Mechteld A.R. Vermeulen; Milan C. Richir; Mariska Davids; Willem Wisselink; Bas A.J.M. de Mol; Paul A.M. van Leeuwen


Eur J Heart Fail. 2010;12(12):1274-1281. 

In This Article

Arginine Metabolism

Dietary arginine is absorbed in the small intestine and is taken up from the circulation by CAT into the liver, kidney, and endothelial cells. Besides dietary intake, arginine availability depends on endogenous release through protein degradation, on synthesis from citrulline by the enzymes argininosuccinate synthase (ASS) and argininosuccinate lyase (ASL), and the conversion of glutamine into citrulline, which can be converted into arginine in the kidney (Figure 1).

Arginine can be incorporated into proteins by the enzyme arginyl-tRNA synthetase (ATS) or can be used as a substrate in four metabolic pathways (Figure 1). First, arginine can be converted into agmatine by arginine decarboxylase (ADC). The second metabolic pathway is creatine synthesis by the conversion of arginine by arginine glycine amidinotransferase (AGAT) to guanidinoacetic acid, which is converted to creatine. Creatine is converted into creatine phosphate, which is an important form of stored energy in (cardiac) muscle tissue. The third pathway is the conversion of arginine into NO and citrulline facilitated by NOS. Nitric oxide can subsequently diffuse into the vascular smooth muscle layer resulting in cGMP-mediated relaxation and vasodilation. Although the concentration of arginine in endothelial cells is higher than necessary to saturate NOS, it has been shown that increased extracellular arginine can be taken up by endothelial cells and can contribute to NO production, a phenomenon called 'the arginine paradox'.[3] The arginine/ADMA ratio might play a role in this paradox since this ratio reflects the amount of substrate (arginine) relative to inhibitor of NOS (ADMA), which can be considered as a better indicator of NO production than ADMA or arginine concentration separately. The last metabolic pathway of arginine is its conversion into urea and ornithine by the enzyme arginase. Two isoforms of arginase are known: type I metabolizes arginine in the cytosol, whereas type II is active in the mitochondria. Ornithine can be converted into polyamines by the enzyme ornithine decarboxylase (ODC) and into proline and glutamate by ornithine aminotransferase (OAT).


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