Cellular ADMA: regulation and action

Abstract

Asymmetric (N(G),N(G)) dimethylarginine (ADMA) is present in plasma and cells. It can inhibit nitric oxide synthase (NOS) that generates nitric oxide (NO) and cationic amino acid transporters (CATs) that supply intracellular NOS with its substrate, l-arginine, from the plasma. Therefore, ADMA and its transport mechanisms are strategically placed to regulate endothelial function. This could have considerable clinical impact since endothelial dysfunction has been detected at the origin of hypertension and chronic kidney disease (CKD) in human subjects and may be a harbinger of large vessel disease and cardiovascular disease (CVD). Indeed, plasma levels of ADMA are increased in many studies of patients at risk for, or with overt CKD or CVD. However, the levels of ADMA measured in plasma of about 0.5micromol.l(-1) may be below those required to inhibit NOS whose substrate, l-arginine, is present in concentrations many fold above the Km for NOS. However, NOS activity may be partially inhibited by cellular ADMA. Therefore, the cellular production of ADMA by protein arginine methyltransferase (PRMT) and protein hydrolysis, its degradation by N(G),N(G)-dimethylarginine dimethylaminohydrolase (DDAH) and its transmembrane transport by CAT that determines intracellular levels of ADMA may also determine the state of activation of NOS. This is the focus of the review. It is concluded that cellular levels of ADMA can be 5- to 20-fold above those in plasma and in a range that could tonically inhibit NOS. The relative importance of PRMT, DDAH and CAT for determining the intracellular NOS substrate:inhibitor ratio (l-arginine:ADMA) may vary according to the pathophysiologic circumstance. An understanding of this important balance requires knowledge of these three processes that regulate the intracellular levels of ADMA and arginine.

Figure 1

Overview of some pathways for ADMA generation, metabolism, transport and excretion.

Figure 2

Data from studies showing intracellular L-arginine in brain in relation to the Km for nNOS and the Kt for CAT-1 (Panel A), and for intracellular ADMA in brain in relation to the Ki for nNOS (Panel B) and for intracellular ADMA in endothelial cells from normal or diabetic animals in relation to the Ki for eNOS. Panel A and B: Redrawn from data in Cardounel, AJ and Zweier, JL. Endogenous methylarginines regulate neuronal nitric-oxide synthase and prevent excitotoxic injury. J Biol Chem 277: 33995–34002, 2002. Panel C: Redrawn from data in (1) Bogle, RG et al. Induction of NG-monomethyl-L-arginine uptake: a mechanism for differential inhibition of NO synthases? Am J Physiol 269: C750–C756, 1995. (2) Masuda, H et al. Accelerated intimal hyperplasia and increased endogenous inhibitors for NO synthesis in rabbits with alloxan-induced hyperglycaemia. Br J Pharmacol 126: 211–218, 1999. (3) MacAllister, RJ et al. Effects of guanidino and uremic compounds on nitric oxide pathways. Kidney Int 45: 737–742, 1994.

Figure 3

Diagrammatic representation of some factors described in the text that have been reported to change the expression and/or activity of CAT-1 or CAT-2 isoforms.

Figure 4

Simplified scheme of ADMA metabolism. Both free ADMA and SDMA are generated upon proteolysis of methylated proteins and may leave the cell via cationic amino acids transporters (CAT). In addition, ADMA is hydrolyzed by dimethylarginine dimethyaminohydrolase (DDAH) into citrulline and dimethylamine (DMA). Distinct changes in intra- and extracellular levels of ADMA, SDMA, and DMA may occur upon increased protein methylation and/or proteolysis (left panel), decreased DDAH activity (middle panel) or decreased CAT activity (right panel). See text for a detailed description.