This article is part of the Research Topic The role of arginase in endothelial dysfunction

Mini Review ARTICLE

Front. Immunol., 09 July 2013 |

The subcellular compartmentalization of arginine metabolizing enzymes and their role in endothelial dysfunction

  • 1Vascular Biology Center, Georgia Regents University, Augusta, GA, USA
  • 2Department of Pharmacology, Georgia Regents University, Augusta, GA, USA

The endothelial production of nitric oxide (NO) mediates endothelium-dependent vasorelaxation and restrains vascular inflammation, smooth muscle cell proliferation, and platelet aggregation. Impaired production of NO is a hallmark of endothelial dysfunction and promotes the development of cardiovascular disease. In endothelial cells, NO is generated by endothelial nitric oxide synthase (eNOS) through the conversion of its substrate, L-arginine to L-citrulline. Reduced access to L-arginine has been proposed as a major mechanism underlying reduced eNOS activity and NO production in cardiovascular disease. The arginases (Arg1 and Arg2) metabolize L-arginine to generate L-ornithine and urea and increased expression of arginase has been proposed as a mechanism of reduced eNOS activity secondary to the depletion of L-arginine. Indeed, supplemental L-arginine and suppression of arginase activity has been shown to improve endothelium-dependent relaxation and ameliorate cardiovascular disease. However, this simple relationship is complicated by observations that L-arginine concentrations in endothelial cells remain sufficiently high to support NO synthesis. Accordingly, the subcellular compartmentalization of intracellular L-arginine into poorly interchangeable pools has been proposed to allow for the local depletion of pools or pockets of L-arginine. In agreement with this, there is considerable evidence supporting the importance of the subcellular localization of L-arginine metabolizing enzymes. In endothelial cells in vitro and in vivo, eNOS is found in discrete intracellular locations and the capacity to generate NO is heavily influenced by its localization inside the cell. Arg1 and Arg2 also reside in different subcellular environments and are thought to differentially influence endothelial function. The plasma membrane solute transporter, CAT-1 and the arginine recycling enzyme, arginosuccinate lyase, co-localize with eNOS and facilitate NO release. Herein, we highlight the importance of the subcellular location of eNOS and arginine transporting and metabolizing enzymes to NO release and cardiovascular disease.

Keywords: eNOS, L-arginine, nitric, arginase, CAT-1, ASL, ASS, L-citrulline

Citation: Chen F, Lucas R and Fulton D (2013) The subcellular compartmentalization of arginine metabolizing enzymes and their role in endothelial dysfunction. Front. Immunol. 4:184. doi: 10.3389/fimmu.2013.00184

Received: 13 April 2013; Accepted: 24 June 2013;
Published online: 09 July 2013.

Edited by:

Charles Dinarello, University of Colorado Health Sciences Center, USA

Reviewed by:

Sungwoo Ryoo, Kangwon National University, South Korea
Mark James Crabtree, University of Oxford, UK

Copyright: © 2013 Chen, Lucas and Fulton. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

*Correspondence: David Fulton, Vascular Biology Center, Georgia Regents University, 1459 Laney Walker Bvld., Augusta, GA 30912, USA e-mail: